Prosthesis having varied concentration of beneficial agent

ABSTRACT

An interventional device for delivery of beneficial agent to a lumen and methods of loading and manufacture of the same, which include a prosthesis loaded with beneficial agent to provide a controlled dosage concentration of beneficial agent to the lumen. The beneficial agent is loaded onto the prosthesis by a fluid-dispenser having a dispensing element capable of dispensing the beneficial agent in discrete droplets, each droplet having a controlled trajectory. The interventional device has a controlled local areal density of beneficial agent for systemic delivery or delivery to the luminal wall. The local areal density of beneficial agent may be varied along the prosthesis. The interventional device includes overlapping or bifurcated stents having a controlled areal density of beneficial agent.

RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional PatentApplications Ser. Nos. 60/424,574; 60/424,575; 60/424,576; 60/424,577;and 60/424,607, each of which was filed on Nov. 7, 2002, and each ofwhich is incorporated herein by reference thereto.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] The present invention relates to an interventional device havinga varied concentration of beneficial agent along its length and inparticular to an interventional device having a first portion having alocal areal density of beneficial agent that is different than the localareal density of beneficial agent loaded onto a second portion of theinterventional device. The invention also relates to an interventionaldevice for delivery of a controlled local areal density of beneficialagent, particularly across multiple prostheses.

[0004] 2. Description of Related Art

[0005] Percutaneous transluminal coronary angioplasty (PTCA) is aprocedure for treating heart disease. This procedure generally entailsintroducing a catheter assembly into the cardiovascular system of apatient via the brachial or femoral artery, and advancing the catheterassembly through the coronary vasculature until a balloon portionthereon is positioned across an occlusive lesion. Once in positionacross the lesion, the balloon is inflated to a predetermined size toradially compress against the atherosclerotic plaque of the lesion toremodel the vessel wall. Subsequently, the balloon is deflated to allowthe catheter assembly to be withdrawn from the vasculature.

[0006] While PCTA is widely used, it suffers from two unique problems.First, the blood vessel may suffer acute occlusion immediately after orwithin the initial hours after the dilation procedure. Such occlusion isreferred to as “abrupt closure.” Abrupt closure occurs in approximatelyfive percent of cases in which PTCA is employed. The primary mechanismsof abrupt closures are believed to be elastic recoil, arterialdissection and/or thrombosis. The second problem associated with thisprocedure is the re-narrowing of an artery after an initially successfulangioplasty. This re-narrowing is referred to as “restenosis,” whichtypically occurs within the first six months after angioplasty.Restenosis is believed to be due to, among other things, theproliferation and migration of cellular components from the arterialwall, as well as through geometric changes in the arterial wall referredto as “remodeling.”

[0007] To reduce occlusion of the artery, and the development ofthrombosis and/or restenosis, an expandable interventional device orprosthesis, one example of which includes a stent, is implanted in thelumen to maintain the vascular patency. Additionally, to bettereffectuate the treatment of such vascular disease, it is preferable toload an intraluminal device or prosthesis with one or more beneficialagents, such as antiproliferatives, for delivery to a lumen. Onecommonly applied technique for the local delivery of a drug is throughthe use of a polymeric carrier coated onto the surface of a stent, asdisclosed in Berg et al., U.S. Pat. No. 5,464,650, the disclosure ofwhich is incorporated herein by reference. Such conventional methods andproducts generally have been considered satisfactory for their intendedpurpose. However, some problems associated with such drug elutinginterventional devices is the variability in drug loading across aninterventional device, as well as the variability in drug concentrationfrom device to device. Other disadvantages include the inability totightly control and maintain drug concentration, the inability to verifydrug distribution or drug loading on any given device, the inability tovary drug distribution in a controlled and predetermined manner toeffect a more desirable drug loading profile, the inability to loaddifferent, and in particular incompatible or reactive drugs onto thesame surface of a device, and the difficulty in controlling the localareal density of beneficial agent that is delivered to the lumen,particularly if the interventional device is an overlapping orbifurcated device coated with beneficial agent.

[0008] As evident from the related art, conventional methods of loadinginterventional devices with beneficial agents, such as drugs, oftenrequires coating the entire prosthesis with a polymer capable ofreleasing therapeutic drugs, as disclosed in Campbell, U.S. Pat. No.5,649,977 and Dinh et al., U.S. Pat. No. 5,591,227, the disclosures ofwhich are incorporated herein by reference. Because certaininterventional devices may a have varied surface area along its length,such conventional loading techniques results in unintentional orundesirable dosage variations. Additionally, if it is desired tosuperimpose two or more conventionally-loaded prostheses, such as withnested stents or bifurcated stents, the total dosage of beneficial agentto the lumen will exceed the nominal or desired dosage. Another drawbackof the conventional methods of loading interventional devices withbeneficial agents is the lack of selective dosing, such as providingvarious beneficial agents or various concentrations of the samebeneficial agent at different locations on a prosthesis to effect atherapy at specific targeted sites.

[0009] Thus, there remains a need for efficient and economic methods forcontrolling the loading of beneficial agent onto a prosthesis so as toprovide an interventional device having a varied distribution profile ofbeneficial agent to effect therapy at targeted locations of the lumen.Additionally, there is a need for an interventional device capable ofproviding combination therapy of two or more beneficial agents loaded ondifferent surfaces of a prosthesis to effectuate systemic release aswell as release to the wall of the lumen. Further, a need exists for theloading of incompatible beneficial agents onto the same surface of aprosthesis. The advantages of the present invention satisfy theaforementioned needs.

SUMMARY OF THE INVENTION

[0010] The purpose and advantages of the present invention will be setforth in and will become apparent from the description that follows, aswell as will be learned by practice of the invention.

[0011] Additional advantages of the invention will be realized andattained by the methods and systems particularly pointed out in thewritten description and claims hereof, as well as from the appendeddrawings.

[0012] To achieve these and other advantages and in accordance with thepurpose of the invention, as embodied and broadly described, theinvention includes an interventional device for delivery of beneficialagent. The device comprises a prosthesis including a tubular body whendeployed in a lumen. The prosthesis has a first portion and a secondportion and is at least partially loaded with beneficial agent to definea controlled local areal density of beneficial agent. The controlledlocal areal density of beneficial agent is different at the firstportion than at the second portion. The tubular body can be defined by aplurality of interconnected structural members. The first portion of theprosthesis can be a selected set of the interconnected structuralmembers. The selected set of interconnected structural members candefine at least one ring-shaped element extending around a circumferenceof the tubular body.

[0013] In accordance with a further aspect of the invention, aninterventional device for delivery of beneficial agent is providedwherein the first portion of the prosthesis is defined by a first lengthof the tubular body and the second portion of the prosthesis is definedby a second length of the tubular body. The local areal density ofbeneficial agent can be uniform across at least one of the first portionand the second portion. The local areal density of beneficial agent alsocan be varied across at least one of the first portion and the secondportion. Furthermore, the beneficial agent of at least one of the firstportion and the second portion can be loaded by a fluid-dispenser. Thebeneficial agent can be mixed with a binder prior to being loaded by thefluid-dispenser. Also, the ratio of beneficial agent to binder can bevaried to vary the local areal density of beneficial agent loaded on theprosthesis. The amount of mixture of beneficial agent and binder appliedcan be varied to vary the local areal density of beneficial agent loadedon the prosthesis.

[0014] In accordance with another aspect of the invention, aninterventional device for delivery of beneficial agent is providedwherein prosthesis includes a layer of a base material on a surface ofthe tubular body, the beneficial agent being loaded to the base materiallayer. The base material layer can define a pattern for loading thebeneficial agent. Preferably, the base material layer includesdexamethasone.

[0015] In accordance with still a further aspect of the invention, theprosthesis is selected from a group consisting of a stent, graft,stent-graft, filter and other intravascular devices.

[0016] The beneficial agent includes but is not limited toantithrombotics, anticoagulants, antiplatelet agents, anti-lipid agents,thrombolytics, antiproliferatives, anti-inflammatories, agents thatinhibit hyperplasia, smooth muscle cell inhibitors, antibiotics, growthfactor inhibitors, cell adhesion inhibitors, cell adhesion promoters,antimitotics, antifibrins, antioxidants, antineoplastics, agents thatpromote endothelial recovery, antiallergic substances, radiopaqueagents, viral vectors, antisense compounds, oligionucleotides, cellpermeation enhancers, angiogenesis agents and combinations thereof.

[0017] The beneficial agent includes but is not limited to rapamycin,paclitaxel, estradiol, and the rapamycin analog known as ABT-578, i.e.,3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Hexadecahydro-9,27-dihydroxy-3-[(1R)-2-[(1S,3R,4R)-3-methoxy-4-tetrazol-1-yl)cyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone;23,27-Epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone.

[0018] In accordance with yet a further aspect of the invention, aninterventional device for delivery of beneficial agent is providedwherein the beneficial agent is mixed with a solvent. The solvent can beisobutanol.

[0019] The invention also provides for an interventional device fordelivery of beneficial agent, wherein the device comprises a prosthesisincluding a tubular body when deployed in a lumen. The prosthesis is atleast partially loaded with a beneficial agent having a local arealdensity that is varied along a selected portion of the tubular body. Thelocal areal density of beneficial agent can be varied as a continuousgradient along the selected portion of the tubular body. The local arealdensity of beneficial agent can be varied so as to have a first localareal density of beneficial agent at at least one end section of theprosthesis and a second local areal density of beneficial agent at anintermediate section of the prosthesis, wherein the first local arealdensity can be different than the second local areal density. The firstlocal areal density can be less than the second local areal density. Thelocal areal density of beneficial agent can also be varied to correspondwith a location of a lesion when the prosthesis is deployed in a lumen.

[0020] In accordance with a further aspect of the invention, thebeneficial agent is loaded by a fluid-dispenser.

[0021] In accordance with another aspect of the invention, aninterventional device for delivery of beneficial agent is providedwherein the beneficial agent is mixed with a binder prior to beingloaded by the fluid-dispenser. The ratio of beneficial agent to bindercan be varied to vary the local areal density of beneficial agent loadedon the prosthesis. The amount of mixture of beneficial agent and binderapplied can also be varied to vary the local areal density of beneficialagent loaded on the prosthesis.

[0022] In accordance with a further aspect of the invention, a method ofmanufacturing an interventional device for delivery of beneficial agentis provided, wherein the method comprises the steps of providing aprosthesis including a tubular body when deployed within a lumen wherethe prosthesis has a first portion and a second portion; providingbeneficial agent to be delivered from the prosthesis; and loading theprosthesis with beneficial agent to define a controlled local arealdensity of beneficial agent. The controlled local areal density ofbeneficial agent at the first portion preferably is different than atthe second portion.

[0023] In accordance with another aspect of the invention, a method ofmanufacturing an interventional device for delivery of beneficial agentis provided, wherein the tubular body of the prosthesis is defined by aplurality of interconnected structural members, the first portion of theprosthesis being a selected set of the interconnected structuralmembers. The set of interconnected structural members define at leastone ring-shaped element extending around a circumference of the tubularbody. The first portion of the prosthesis provided by the providing stepcan be defined by a first length of the tubular body and the secondportion of the prosthesis can be defined by a second length of thetubular body. In accordance with yet another aspect of the invention, amethod of manufacturing an interventional device for delivery ofbeneficial agent is provided, wherein the loading step can includedefining a uniform local areal density of beneficial agent across atleast one of the first portion and the second portion. The loading stepcan also include defining a varied local areal density of beneficialagent across at least one of the first portion and the second portion.The loading step can be performed by a fluid-dispenser. The loading stepcan also include mixing the beneficial agent with a binder prior tobeing loaded by the fluid-dispenser.

[0024] The method can also include the step of applying a layer of abase material on a surface of the tubular body and the loading step mayinclude introducing the beneficial agent to the base material layer. Theapplying step can be performed to define a pattern for loading thebeneficial agent on a selected surface of the prosthesis.

[0025] In accordance with still a further aspect of the invention, amethod of manufacturing an interventional device for delivery ofbeneficial agent is provided, where the method comprises the steps ofproviding a prosthesis having a tubular body when deployed in a lumen;providing beneficial agent to be delivered from the prosthesis; andloading the beneficial agent on the prosthesis to define a local arealdensity that is varied along a selected portion of the tubular body.

[0026] In accordance with yet another aspect of the invention, a methodof manufacturing an interventional device for delivery of beneficialagent is provided, wherein the varied local areal density of beneficialagent loaded by the loading step is defined as a continuous gradientalong the selected portion of the tubular body. The varied local arealdensity of beneficial agent loaded by the loading step may include afirst local areal density of beneficial agent at at least one endsection of the prosthesis and a second local areal density of beneficialagent at an intermediate section of the prosthesis, the first localareal density being different than the second local areal density. Thevaried local areal density of beneficial agent loaded by the loadingstep can be varied to correspond to a location of a lesion when theprosthesis is deployed in a lumen. The loading step can be performed bya fluid-dispenser, and the loading step may include mixing thebeneficial agent with a binder prior to being loaded by thefluid-dispenser. The binder preferably is biodegradable. The loadingstep can also include varying the ratio of beneficial agent to binder tovary the local areal density along the selected portion of the tubularbody. The loading step can also include varying an amount of mixture ofbeneficial agent and binder to vary the local areal density along theselected portion of the tubular body.

[0027] The method can further include the step of applying a layer of abase material on a surface of the tubular body and the loading step caninclude introducing the beneficial agent to the base material layer. Theapplying step can be performed to define a pattern of base material forloading the beneficial agent on a selected surface of the prosthesis.The loading step can also include applying the beneficial agentuniformly to the prosthesis and selectively extracting from theprosthesis amounts of beneficial agent from the selected portion of thetubular body to define the varied local areal density.

[0028] In yet another aspect of the invention, the invention includes aninterventional device for delivery of a beneficial agent, theinterventional device comprising a first prosthesis to be deployed in alumen; a second prosthesis configured to be deployed in an overlappingrelationship with the first prosthesis; the first prosthesis and thesecond prosthesis, in combination, defining at least one non-overlappingsegment and an overlapping segment; and the first prosthesis and thesecond prosthesis loaded with beneficial agent to provide a controlledlocal areal density across a length of the first prosthesis and thesecond prosthesis in combination.

[0029] In another aspect of the invention, an interventional device isprovided wherein the controlled local areal density is uniform along thelength of the first prosthesis and the second prosthesis in combination.Preferably, the controlled local areal density of beneficial agent isvaried along the length of the first prosthesis and the secondprosthesis in combination. More preferably, the controlled local arealdensity of beneficial agent of the non-overlapping segment is greaterthan the controlled local areal density of beneficial agent of theoverlapping segment.

[0030] In another aspect of the invention, an interventional device isprovided wherein the first prosthesis has a first portion correspondingto the overlapping segment of the first prosthesis and second prosthesisin combination; a second portion corresponding to the at least onenon-overlapping segment of the first prosthesis and second prosthesis incombination; and at least one of the first portion and the secondportion of the first prosthesis is loaded with beneficial agent.Preferably, the first portion of the first prosthesis has a local arealdensity of beneficial agent different than the local areal density ofbeneficial agent of the second portion of first prosthesis.

[0031] In still another aspect of the invention, an interventionaldevice is provided wherein the beneficial agent is impregnated onto atleast one of the first prosthesis and the second prosthesis.

[0032] In a further aspect of the invention, an interventional device isprovided wherein the beneficial agent is coated onto at least one of thefirst prosthesis and the second prosthesis. The beneficial agent may becoated onto a selected surface of at least one of the first prosthesisand the second prosthesis by a fluid-dispenser having a dispensingelement capable of dispensing beneficial agent in discrete droplets,each having a controlled trajectory. The beneficial agent can also becoated onto at least one of the first prosthesis and the secondprosthesis by applying a coating material layer to a selected surface ofat least one of the first prosthesis and the second prosthesis andintroducing beneficial agent to the coating material layer. The coatingmaterial can be applied to a selected surface of at least one of thefirst prosthesis and the second prosthesis to define a pattern for thecontrolled local areal density of beneficial agent from the firstprosthesis and the second prosthesis in combination.

[0033] In yet another aspect of the invention, an interventional deviceis provided wherein at least two different beneficial agents are loadedon at least one of the first prosthesis and the second prosthesis. Theat least two beneficial agents may be dispensed as separate unmixeddroplets to load the at least one of the first prosthesis and secondprosthesis.

[0034] In another aspect of the invention, an interventional device isprovided wherein the first prosthesis and second prosthesis incombination define a bifurcated stent.

[0035] The invention also includes a method of manufacturing aninterventional device for delivery of beneficial agent, the methodcomprising the steps of providing a first prosthesis to be deployedwithin a lumen; providing a second prosthesis configured to be deployedin an overlapping relationship with the first prosthesis, the firstprosthesis and the second prosthesis in combination defining at leastone non-overlapping segment and an overlapping segment; and loading thefirst prosthesis and the second prosthesis with beneficial agent toprovide a controlled local areal density along a length of the firstprosthesis and the second prosthesis in combination.

[0036] The loading step can include providing controlled local arealdensity of beneficial agent that is uniform along the length of thefirst prosthesis and the second prosthesis in combination. The loadingstep can also include providing controlled local areal density ofbeneficial agent that is varied along the length of the first prosthesisand the second prosthesis in combination. The loading step also caninclude providing a greater controlled local areal density of beneficialagent on the non-overlapping segment than on the overlapping segment.

[0037] The beneficial agent provided by the loading step can be selectedfrom a group consisting of antithrombotics, anticoagulants, antiplateletagents, anti-lipid agents, thrombolytics, antiproliferatives,anti-inflammatories, agents that inhibit hyperplasia, smooth muscle cellinhibitors, antibiotics, growth factor inhibitors, cell adhesioninhibitors, cell adhesion promoters, antimitotics, antifibrins,antioxidants, antineoplastics, agents that promote endothelial cellrecovery, antiallergic substances, radiopaque agents, viral vectors,antisense compounds, oligionucleotides, cell permeation enhancers,angiogenesis agents and combinations thereof.

[0038] The loading step can also include impregnating the beneficialagent onto at least one of the first prosthesis and the secondprosthesis. In addition, the loading step can include coating thebeneficial agent on at least one of the first prosthesis and the secondprosthesis. In a further aspect of the invention, the loading step caninclude coating the beneficial agent onto a selected surface of at leastone of the first prosthesis and the second prosthesis by fluid-dispenserhaving a dispensing element capable of dispensing beneficial agent indiscrete droplets, each having a controlled trajectory. Also, theloading step can include coating the beneficial agent onto at least oneof the first prosthesis and the second prosthesis by applying a coatingmaterial layer to a selected surface of at least one of the firstprosthesis and the second prosthesis, and introducing beneficial agentto the coating material layer.

[0039] The applying step can include applying the coating material layerto a selected surface of at least one of the first prosthesis and thesecond prosthesis to define a pattern for the controlled local arealdensity of beneficial agent from the first prosthesis and the secondprosthesis in combination.

[0040] In another aspect of the invention, the loading step can includeloading at least two different beneficial agents onto at least one ofthe first prosthesis and the second prosthesis. The loading step mayinclude dispensing the at least two beneficial agents as separateunmixed droplets onto at least one of the first prosthesis and thesecond prosthesis.

[0041] In still another aspect of the invention, an interventionaldevice to be deployed within a lumen is provided, wherein the devicecomprises a first prosthesis including a tubular body having a firstportion and a second portion when deployed; the first prosthesis atleast partially loaded with beneficial agent; one of the first portionand the second portion having a local areal density of beneficial agentdifferent than a local areal density of beneficial agent of the otherportion.

[0042] In accordance with one aspect of the invention, the loadedbeneficial agent is impregnated onto the first prosthesis. In accordancewith another aspect of the invention, the loaded beneficial agent is becoated onto the first prosthesis. In a further aspect of the invention,the beneficial agent may be coated onto a selected surface of the firstprosthesis by a fluid-dispenser having a dispensing element capable ofdispensing beneficial agent in discrete droplets, each having acontrolled trajectory. The beneficial agent also can be coated onto thefirst prosthesis by applying a coating material layer to a selectedsurface of the first prosthesis and introducing beneficial agent to thecoating material layer. In another aspect of the invention, the coatingmaterial is applied to a selected surface to define a pattern forloading the beneficial agent on the first prosthesis. In addition, atleast two different beneficial agents can be loaded on the firstprosthesis.

[0043] In a further aspect of the invention, an interventional device isprovided further comprising a second prosthesis, wherein the secondprosthesis includes a tubular body at least partially loaded withbeneficial agent. In this aspect of the invention, the first prosthesisand second prosthesis, in combination, define at least onenon-overlapping segment and an overlapping segment, wherein the firstportion of the first prosthesis and a first portion of the secondprosthesis are in an overlapping relationship when deployed within alumen; and the beneficial agent is loaded to provide a controlled localareal density across a length of the first prosthesis and the secondprosthesis in combination. The controlled local areal density ofbeneficial agent can be uniform along the length of the first prosthesisand the second prosthesis in combination. Alternatively, the controlledlocal areal density of beneficial agent can be varied along the lengthof the first prosthesis and the second prosthesis in combination.

[0044] A method of delivering beneficial agent is also provided, whereinthe method comprises the steps of providing a first prosthesis having atubular body when deployed in a lumen; providing a second prosthesishaving a tubular body when deployed in a lumen; loading at least one ofthe first prosthesis and the second prosthesis with beneficial agent;deploying the first prosthesis into a lumen; deploying the secondprosthesis into the lumen to define in combination with the firstprosthesis at least one non-overlapping segment and an overlappingsegment; wherein the beneficial agent is loaded onto at least one of thefirst prosthesis and the second prosthesis to provide a controlled localareal density of beneficial agent across a length of the firstprosthesis and the second prosthesis when deployed.

[0045] The loading step can include loading the first prosthesis and thesecond prosthesis to provide a controlled local areal density ofbeneficial agent that is uniform along the length of the firstprosthesis and the second prosthesis in combination. Alternatively, theloading step can include loading the first prosthesis and the secondprosthesis to provide a controlled local areal density of beneficialagent that is varied along the length of the first prosthesis and thesecond prosthesis in combination. In a further aspect of the invention,the loading step may include providing a greater controlled local arealdensity of beneficial agent on the non-overlapping segment than on theoverlapping segment.

[0046] It is to be understood that both the foregoing generaldescription and the following detailed description are exemplary and areintended to provide further explanation of the invention claimed.

[0047] The accompanying Figures, which are incorporated in andconstitute part of this specification, are included to illustrate andprovide a further understanding of the method and system of theinvention. Together with the description, the Figures serve to explainthe principles of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

[0048]FIGS. 1a-1 c are schematic representations of a prosthesis loadedwith beneficial agent having a first portion and a second portion havingdifferent local areal densities of beneficial agent in accordance withthe present invention, and graphs depicting corresponding areal density.

[0049]FIG. 2 is a schematic representation of a first prosthesis and asecond prosthesis configured to define a nested interventional device,each at least partially loaded with beneficial agent in accordance withthe present invention.

[0050]FIG. 3 is a schematic representation of the first prosthesis andsecond prosthesis of FIG. 2, deployed in overlapping relationship toprovide a controlled local areal density across the length of theinterventional device.

[0051]FIG. 4 is a schematic representation of a first prosthesis andsecond prosthesis configured to define a bifurcated interventionaldevice, each at least partially loaded with beneficial agent inaccordance with the present invention.

[0052]FIG. 5 is a schematic representation of the first prosthesis andsecond prosthesis of FIG. 4, deployed in an overlapping relationship toprovide a bifurcated interventional device having a controlled localareal density across a length of the interventional device.

[0053]FIG. 6 is a schematic representation of an interventional device,and FIG. 6a is a detail schematic depicting a raster format for loadingbeneficial agent thereon.

[0054]FIG. 7 is a schematic representation of an embodiment of thesystem of the present invention.

[0055]FIGS. 8a-8 d are schematic representations of an “off-axis”dispensing method at various cross-sections of the device of FIG. 6.

[0056]FIG. 9 is a schematic representation of another embodiment of thesystem of the present invention.

[0057]FIG. 10 is a schematic representation of discrete droplets loadedin an overlapping manner.

[0058]FIG. 11 is a schematic representation of a method of loadingbeneficial agent on an inner surface of an interventional device.

[0059]FIG. 12 is a schematic representation of the cross-section of thestructural element of a prosthesis having a cavity therein.

[0060]FIG. 13 is a schematic representation of the holding tool assemblyof the system of the invention, FIG. 13a is a detail schematic depictingthe holding tool assembly including the spindle.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0061] Reference will now be made in detail to the present preferredembodiments of the method and system for loading beneficial agent onto aprosthesis, and the interventional devices loaded with beneficial agent.Wherever possible, the same reference characters will be used throughoutthe drawings to refer to the same or like parts.

[0062] In accordance with the present invention, an interventionaldevice is provided for delivery of beneficial agent within a lumen.Particularly, the present invention is suited for providing aninterventional device having a controlled areal density of beneficialagent for the treatment and prevention of vascular or other intraluminaldiseases. Generally, “controlled areal density” is understood to mean aknown or predetermined amount of beneficial agent, either by weight orvolume, over a unit surface area of the interventional device.

[0063] As used herein “interventional device” refers broadly to anydevice suitable for intraluminal delivery or implantation. For purposesof illustration and not limitation, examples of such interventionaldevices include stents, grafts, stent-grafts, filters, and the like. Asis known in the art, such devices may comprise one or more prostheses,each having a first cross-sectional dimension or profile for the purposeof delivery and a second cross-sectional dimension or profile afterdeployment. Each prosthesis may be deployed by known mechanicaltechniques such as balloon expansion deployment techniques, or byelectrical or thermal actuation, or self-expansion deploymenttechniques, as well known in the art. Examples of such for purpose ofillustration include U.S. Pat. No. 4,733,665 to Palmaz; U.S. Pat. No.6,106,548 to Roubin et al.; U.S. Pat. No. 4,580,568 to Gianturco; U.S.Pat. No. 5,755,771 to Penn et al.; and U.S. Pat. No. 6,033,434 toBorghi, all of which are incorporated herein by reference.

[0064] For purposes of explanation and illustration, and not limitation,an exemplary embodiment of the interventional device in accordance withthe invention is shown schematically in FIG. 1a. In accordance with oneaspect of the invention, as shown schematically in FIG. 1, theinterventional device generally includes a prosthesis 10 loaded withbeneficial agent to provide a local areal density of beneficial agentacross a length of the interventional device. Particularly, as embodiedherein the prosthesis may be a stent, a graft, a stent-graft, a filter,or the like, as previously noted, for intravascular or coronary deliveryand/or implantation. However, the prosthesis may be any type ofintraluminal member capable of being loaded with beneficial agent.

[0065] The prosthesis can be in an expanded or unexpanded state duringthe loading of beneficial agent. The underlying structure of theprosthesis can be virtually any structural design and the prosthesis canbe composed any suitable material such as, but not limited to, stainlesssteel, “MP35N,” “MP20N,” elastinite (Nitinol), tantalum, nickel-titaniumalloy, platinum-iridium alloy, gold, magnesium, polymer, ceramic,tissue, or combinations thereof. “MP35N” and “MP20N” are understood tobe trade names for alloys of cobalt, nickel, chromium and molybdenumavailable from Standard Press Steel Co., Jenkintown, Pa. “MP35N”consists of 35% cobalt, 35% nickel, 20% chromium, and 10% molybdenum.“MP20N” consists of 50% cobalt, 20% nickel, 20% chromium and 10%molybdenum. The prosthesis can be made from bioabsorbable or biostablepolymers. In some embodiments, the surface of the prosthesis can includeone or more reservoirs or cavities formed therein, as described furtherbelow.

[0066] The prosthesis can be fabricated utilizing any number of methodsknown in the art. For example, the prosthesis can be fabricated from ahollow or formed tube that is machined using lasers, electric dischargemilling, chemical etching or other known techniques. Alternatively, theprosthesis can be fabricated from a sheet that is rolled into a tubularmember, or formed of a wire or filament construction as known in theart.

[0067] As noted above, the prosthesis is at least partially loaded withbeneficial agent (10 a, 10 b, 10 c). “Beneficial agent” as used herein,refers to any compound, mixture of compounds, or composition of matterconsisting of a compound, which produces a beneficial or useful result.The beneficial agent can be a polymer, a marker, such as a radiopaquedye or particles, or can be a drug, including pharmaceutical andtherapeutic agents, or an agent including inorganic or organic drugswithout limitation. The agent or drug can be in various forms such asuncharged molecules, components of molecular complexes,pharmacologically-acceptable salts such as hydrochloride, hydrobromide,sulfate, laurate, palmitate, phosphate, nitrate, borate, acetate,maleate, tartrate, oleate, and salicylate.

[0068] An agent or drug that is water insoluble can be used in a formthat is a water-soluble derivative thereof to effectively serve as asolute, and on its release from the device, is converted by enzymes,hydrolyzed by body pH, or metabolic processes to a biologically activeform. Additionally, the agents or drug formulations can have variousknown forms such as solutions, dispersions, pastes, particles, granules,emulsions, suspensions and powders. The drug or agent may or may not bemixed with polymer or a solvent as desired.

[0069] For purposes of illustration and not limitation, the drug oragent can include antithrombotics, anticoagulants, antiplatelet agents,thrombolytics, antiproliferatives, anti-inflammatories, agents thatinhibit hyperplasia, inhibitors of smooth muscle proliferation,antibiotics, growth factor inhibitors, or cell adhesion inhibitors.Other drugs or agents include but are not limited to antineoplastics,antimitotics, antifibrins, antioxidants, agents that promote endothelialcell recovery, antiallergic substances, radiopaque agents, viralvectors, antisense compounds, oligionucleotides, cell permeationenhancers, angiogenesis agents, and combinations thereof.

[0070] Examples of such antithrombotics, anticoagulants, antiplateletagents, and thrombolytics include sodium heparin, low molecular weightheparins, heparinoids, hirudin, argatroban, forskolin, vapriprost,prostacyclin and prostacylin analogues, dextran,D-phe-pro-arg-chloromethylketone (synthetic antithrombin), dipyridamole,glycoprotein IIb/IIIa (platelet membrane receptor antagonist antibody),recombinant hirudin, and thrombin inhibitors such as Angiomax™, fromBiogen, Inc., Cambridge, Mass.; and thrombolytic agents, such asurokinase, e.g., Abbokinase™ from Abbott Laboratories Inc., NorthChicago, Ill., recombinant urokinase and pro-urokinase from AbbottLaboratories Inc., tissue plasminogen activator (Alteplase™ fromGenentech, South San Francisco, Calif. and tenecteplase (TNK-tPA).

[0071] Examples of such cytostatic or antiproliferative agents includerapamycin and its analogs such as everolimus, ABT-578, i.e.,3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Hexadecahydro-9,27-dihydroxy-3-[(1R)-2-[(1S,3R,4R)-3-methoxy-4-tetrazol-1-yl)cyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone;23,27-Epoxy-3Hpyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone,which is disclosed in U.S. Pat. Nos. 6,015,815, 6,329,386, U.S.Publication 2003/129215, filed on Sep. 6, 2002, and U.S. Publication2002/123505, filed Sep. 10, 2001, the disclosures of which are eachincorporated herein by reference thereto, tacrolimus and pimecrolimus,angiopeptin, angiotensin converting enzyme inhibitors such as captopril,e.g, Capoten® and Capozide® from Bristol-Myers Squibb Co., Stamford,Conn., cilazapril or lisinopril, e.g., Prinivil® and Prinzide® fromMerck & Co., Inc., Whitehouse Station, N.J.; calcium channel blockerssuch as nifedipine, amlodipine, cilnidipine, lercanidipine, benidipine,trifluperazine, diltiazem and verapamil, fibroblast growth factorantagonists, fish oil (omega 3-fatty acid), histamine antagonists,lovastatin, e.g. Mevacor® from Merck & Co., Inc., Whitehouse Station,N.J. In addition, topoisomerase inhibitors such as etoposide andtopotecan, as well as antiestrogens such as tamoxifen may be used.

[0072] Examples of such anti-inflammatories include colchicine andglucocorticoids such as betamethasone, cortisone, dexamethasone,budesonide, prednisolone, methylprednisolone and hydrocortisone.Non-steroidal anti-inflammatory agents include flurbiprofen, ibuprofen,ketoprofen, fenoprofen, naproxen, diclofenac, diflunisal, acetominophen,indomethacin, sulindac, etodolac, diclofenac, ketorolac, meclofenamicacid, piroxicam and phenylbutazone.

[0073] Examples of such antineoplastics include alkylating agents suchas altretamine, bendamucine, carboplatin, carmustine, cisplatin,cyclophosphamide, fotemustine, ifosfamide, lomustine, nimustine,prednimustine, and treosulfin, antimitotics such as vincristine,vinblastine, paclitaxel, e.g., TAXOL® by Bristol-Myers Squibb Co.,Stamford, Conn., docetaxel, e.g., Taxotere® from Aventis S.A.,Frankfort, Germany, antimetabolites such as methotrexate,mercaptopurine, pentostatin, trimetrexate, gemcitabine, azathioprine,and fluorouracil, and antibiotics such as doxorubicin hydrochloride,e.g., Adriamycin® from Pharmacia & Upjohn, Peapack, N.J., and mitomycin,e.g., Mutamycin® from Bristol-Myers Squibb Co., Stamford, Conn., agentsthat promote endothelial cell recovery such as Estradiol.

[0074] Additional drugs which may be utilized in this applicationinclude dexamethasone; fenofibrate; inhibitors of tyrosine kinase suchas RPR-101511A; PPAR-alpha agonists such as Tricor™ formulation fromAbbott Laboratories Inc., North Chicago, Ill.; endothelin receptorantagonists such as ABT-627 having general formula C₂₉H₃₈N₂O₆.ClH, andthe following structural formula

[0075] from Abbott Laboratories Inc., North Chicago, Ill., as disclosedin U.S. Pat. No. 5,767,144, the disclosure of which is incorporatedherein by reference; matrix metalloproteinase inhibitors such as ABT-518{[S-(R*,R*)]-N-[1-(2,2-dimethyl-1,3-dioxol-4-yl)-2-[[4-[4-(trifluoro-methoxy)-phenoxy]phenyl]sulfonyl]ethyl]-N-hydroxyformamide},having general formula C₂₁H₂₂F₃NO₈S and having the following structuralformula

[0076] from Abbott Laboratories Inc., North Chicago, Ill., which isdisclosed in U.S. Pat. No. 6,235,786, the disclosure of which isincorporated herein by reference; ABT 620{1-Methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide}, which isdisclosed in U.S. Pat. No. 6,521,658, the disclosure of which isincorporated herein by reference; antiallergic agents such aspermirolast potassium nitroprusside, phosphodiesterase inhibitors,prostaglandin inhibitors, suramin, serotonin blockers, steroids,thioprotease inhibitors, triazolopyrimidine, and nitric oxide.

[0077] While the foregoing beneficial agents are known for theirpreventive and treatment properties, the substances or agents areprovided by way of example and are not meant to be limiting. Further,other beneficial agents that are currently available or may be developedare equally applicable for use with the present invention.

[0078] If desired or necessary, the beneficial agent can include abinder to carry, load, or allow sustained release of an agent, such asbut not limited to a suitable polymer or similar carrier. The term“polymer” is intended to include a product of a polymerization reactioninclusive of homopolymers, copolymers, terpolymers, etc., whethernatural or synthetic, including random, alternating, block, graft,branched, cross-linked, blends, compositions of blends and variationsthereof. The polymer may be in true solution, saturated, or suspended asparticles or supersaturated in the beneficial agent. The polymer can bebiocompatible, or biodegradable.

[0079] For purpose of illustration and not limitation, the polymericmaterial include phosphorylcholine linked macromolecules, such as amacromolecule containing pendant phosphorylcholine groups such aspoly(MPC_(w):LMA_(x):HPMA_(y):TSMA_(z)), where MPC is2-methacryoyloxyethylphosphorylcholine, LMA is lauryl methacrylate, HPMAis hydroxypropyl methacrylate and TSMA is trimethoxysilylpropylmethacrylate, polycaprolactone, poly-D,L-lactic acid, poly-L-lacticacid, poly(lactide-co-glycolide), poly(hydroxybutyrate),poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoester,polyanhydride, poly(glycolic acid), poly(glycolic acid-co-trimethylenecarbonate), polyphosphoester, polyphosphoester urethane, poly(aminoacids), cyanoacrylates, poly(trimethylene carbonate),poly(iminocarbonate), polyalkylene oxalates, polyphosphazenes,polyiminocarbonates, and aliphatic polycarbonates, fibrin, fibrinogen,cellulose, starch, collagen, Parylene®, Parylast®, polyurethaneincluding polycarbonate urethanes, polyethylene, polyethyleneterapthalate, ethylene vinyl acetate, ethylene vinyl alcohol, siliconeincluding polysiloxanes and substituted polysiloxanes, polyethyleneoxide, polybutylene terepthalate-co-PEG, PCL-co-PEG, PLA-co-PEG,polyacrylates, polyvinyl pyrrolidone, polyacrylamide, and combinationsthereof. Non-limiting examples of other suitable polymers includethermoplastic elastomers in general, polyolefin elastomers, EPDM rubbersand polyamide elastomers, and biostable plastic material such as acrylicpolymers, and its derivatives, nylon, polyesters and expoxies.Preferably, the polymer contains pendant phosphoryl groups as disclosedin U.S. Pat. Nos. 5,705,583 and 6,090,901 to Bowers et al. and U.S. Pat.No. 6,083,257 to Taylor et al., which are all incorporated herein byreference.

[0080] The beneficial agent can include a solvent. The solvent can beany single solvent or a combination of solvents. For purpose ofillustration and not limitation, examples of suitable solvents includewater, aliphatic hydrocarbons, aromatic hydrocarbons, alcohols, ketones,dimethyl sulfoxide, tetrahydrofuran, dihydrofuran, dimethylacetamide,acetates, and combinations thereof. Preferably, the solvent is ethanol.More preferably, the solvent is isobutanol. Additionally, in anotheraspect of the invention, multiple beneficial agents are dissolved ordispersed in the same solvent. For purpose of illustration and not forlimitation, dexamethasone, estradiol, and paclitaxel are dissolved inisobutanol. Alternatively, dexamethasone, estradiol, and paclitaxel aredissolved in ethanol. In yet another example, dexamethasone, estradiol,and ABT-578, i.e., the rapamycin analog,3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23-S,26R,27R,34aS)9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Hexadecahydro-9,27-dihydroxy-3-[(1R)-2-[(1S,3R,4R)-3-methoxy-4-tetrazol-1-yl)cyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone;23,27-Epoxy-3H-pyrido[2,1-c] [1,4]oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone, are dissolvedtogether in one solvent. Preferably, the solvent is ethanol. Morepreferably, the solvent is isobutanol.

[0081] Additionally, the beneficial agent includes any of theaforementioned drugs, agents, polymers, and solvents either alone or incombination.

[0082] A number of methods can be used to load the beneficial agent ontothe surface of the prosthesis to provide for a controlled local arealdensity of beneficial agent if performed appropriately. For example, theprosthesis can be constructed to include pores or reservoirs which areimpregnated or filled with beneficial agent or multiple beneficialagents. The pores can be sized or spaced apart to correspond to or limitthe amount of beneficial agent contained therein in accordance with thedesired local areal density pattern along the length of theinterventional device, wherein larger pores or more dense spacing wouldbe provided in such portions intended to have a greater local arealdensity. Alternatively, uniform pores sizes can be provided but theamount of beneficial agent loaded therein is limited accordingly.Additionally, if desired, a membrane of biocompatible material can thenbe applied over the pores or reservoirs for sustained or controlledrelease of the beneficial agent from the pores or reservoirs.

[0083] According to some of the embodiments, the beneficial agent can beloaded directly onto the prosthesis or alternatively, the beneficialagent is loaded onto a base material layer that is applied to a surfaceof the prosthesis. For example and not limitation, a base coating, suchas a binder or suitable polymer, is applied to a selected surface of theprosthesis such that a desired pattern is formed on the prosthesissurface. Beneficial agent is then applied directly to the pattern of thebase material.

[0084] In one aspect of the invention, the desired pattern correspondsto the desired controlled local areal density. For example, a greateramount of base material layer is applied to portions of theinterventional device intended to have a greater local areal density ofbeneficial agent, and a lesser amount of base material is applied toportions of the interventional device intended to have a lower localareal density of beneficial agent.

[0085] Alternatively, a suitable base coating capable of retainingbeneficial agent therein can be applied uniformly over the surface ofthe prosthesis, and then selected portions of the base coating can beloaded with the beneficial agent in accordance with the invention. Agreater amount of beneficial agent would be loaded over a unit surfacearea of the base coating intended to have a greater local areal densityand a lower amount of beneficial agent would be loaded over a unitsurface area intended to have a lower local areal density.

[0086] In yet another embodiment of the present invention, thebeneficial agent can be applied directly to the surface of theprosthesis. Generally a binder or similar component can be required toensure sufficient adhesion. For example, this coating technique caninclude admixing the beneficial agent with a suitable binder or polymerto form a coating mixture, which is then coated onto the surface of theprosthesis. The coating mixture is prepared in higher or lowerconcentrations of beneficial agent as desired, and then applied toselected portions of the prosthesis appropriately.

[0087] In any of the embodiments disclosed herein, a porous orbiodegradable membrane or layer made of biocompatible material can becoated over the beneficial agent for sustained release thereof, ifdesired.

[0088] Conventional coating techniques can be utilized to coat thebeneficial agent onto the surface of the prosthesis such as spraying,dipping or sputtering and still provide the desired effect if performedappropriately. With such techniques, it may be desirable or necessary touse known masking or extraction techniques to control the location andamount in which beneficial agent is loaded. Prior to coating theprosthesis with beneficial agent, optical machine vision inspection ofthe prosthesis preferably is utilized to ensure that no mechanicaldefects exist. Defective prostheses thus can be rejected before wastingbeneficial agent, some of which may be very costly.

[0089] In accordance with one aspect of the invention, however, thebeneficial agent is “printed” onto the surface of the prosthesis by afluid-dispenser having a dispensing element capable of dispensingbeneficial agent in discrete droplets, wherein each droplet has acontrolled trajectory. If desired, printing can be combined withconventional coating techniques such as spraying or dipping.

[0090] “Fluid-dispenser,” as used herein, refers broadly to any devicehaving a dispensing element capable of dispensing fluid in discretedroplets wherein each droplet has a controlled trajectory. For purposesof illustration and not limitation, examples of such fluid-dispensersinclude fluid-jetting and similar fluid dispensing technology devicessuch as a drop-on-demand fluid printer and a charge-and-deflect fluidprinter. However, other fluid-dispensers capable of forming a fluid jetor capable of dispensing discrete droplets having a controlledtrajectory are within the scope of the present invention. In a preferredembodiment, the fluid-dispenser is a fluid-jet print head. Suchequipment is available from MicroFab Technologies of Plano, Tex.

[0091] Fluid-jetting and similar technology provides numerous advantagesnot available with conventional loading techniques. For example, fluidjetting technology can be used to deposit materials, such as chemicalreagents, in controlled volumes onto a substrate at a controlledlocation, as disclosed in U.S. Pat. No. 4,877,745 to Hayes et al.,incorporated herein by reference.

[0092] Fluid jetting can also be used to deposit materials in areproducible way. Fluid-jet based deposition of materials is datadriven, non-contact, and requires no tooling. The “printing” informationcan be created directly from CAD information and stored digitally insoftware or hardware. Thus, no masks or screens are required. As anadditive process with no chemical waste, fluid-jetting isenvironmentally friendly. Other advantages include the efficiency offluid jet printing technology. For example, fluid-jetting can dispensespheres of fluid with diameters of 15-200 um at rates of 1-25,000 persecond for single droplets on demand, and up to 1 MHz for continuousdroplets. See Cooley et al., “Applications of Ink-Jet PrintingTechnology to BioMEMS and Microfluidic Systems,” Proc. SPIE Conf. onMicrofluidics, (October 2001), incorporated herein by reference.

[0093] In accordance with one aspect of the invention, a method ofloading beneficial agent onto a prosthesis for delivery within a lumenis disclosed. The method comprises the steps of providing a prosthesis,beneficial agent to be delivered from the prosthesis, and afluid-dispenser having a dispensing element capable of dispensing thebeneficial agent in discrete droplets, wherein each droplet has acontrolled trajectory. The method further includes creating relativemovement between the dispensing element and the prosthesis to define adispensing path and selectively dispensing the beneficial agent in araster format to a predetermined portion of the prosthesis along thedispensing path. In particular, the beneficial agent is selectivelydispensed from the dispensing element to a predetermined portion of theprosthesis in a raster format along a dispensing path. As used herein“raster format” refers to a continuous or non-continuous dispensingpattern of droplets of beneficial agent dispensed at specific intervals.The relative motion of the dispensing element and the prosthesis to beloaded with beneficial agent creates a dispensing path which includes,for example and as shown in FIG. 6a, a sequential series of linearparallel passes 154 that traverse back and forth along one axis of theprosthesis. The relative motion is continued in a linear manner betweenforward and backward or right to left and left to right or upward anddownward, depending on the frame of reference. A traversal or a pass 154is completed when the relative motion reverses direction. That is,relative motion continues past the prosthesis, and then decelerates,stops, reverses direction and accelerates to a constant velocity. Aftereach pass, the position of the dispensing element 150 or prosthesis 10relative to the dispensing element preferably is changed or incrementedsuch that additional droplets do not impact in the same location duringthe subsequent pass, although a certain degree of overlap may bepermitted. For example, as the dispensing element dispenses thebeneficial agent along the prosthesis, a fluid dispensing width “w” isdefined. The dispensing path defined by the relative movement betweenthe dispensing element and the prosthesis can include a series ofparallel passes wherein each parallel pass has a path width no greaterthan the fluid dispensing width defined by the dispensing element,although a greater path width can be defined if desired.

[0094] Alternatively, the dispensing path created by the relative motionof the dispensing element 150 and the prosthesis 10 can include a singlecontinuous helix that wraps continuously around the prosthesis tubularbody and along the length of the prosthesis. FIG. 10 schematicallydepicts such a helical path. In this manner, selectively fluiddispensing in a raster format similar to that of the linear pathspreviously described can be performed using a helical path if desired.In a preferred embodiment, the direction of travel of relative motionconsists of continuously rotating, for example, the prosthesis 10 to beloaded and then incrementally advancing the dispensing element axiallyalong the prosthesis. Both axial and radial motion preferably beginbefore the prosthesis 10 is aligned with the dispensing element 150 toreceive droplets, so as to enable acceleration of both axes to aconstant velocity, and continues beyond the prosthesis where bothmovements may decelerate, and stop. After each rotation, the position ofthe dispensing element 150 or of the prosthesis 10 relative to thedispensing element is moved or incremented axially such that additionaldroplets of beneficial agent preferably do not impact in the samelocation. Any degree of overlap may be permitted to achieve the desiredareal density of beneficial agent.

[0095] For purpose of illustration of this method, and as shown in FIGS.6 and 7, the prosthesis 10 includes a plurality of interconnectedstructural members 12 defining openings 14 therebetween and thebeneficial agent 15 is dispensed only when the dispensing element 150and the structural members 12 within a predetermined portion of theprosthesis 10 are aligned with each other. Accordingly, in thispreferred embodiment, dispensing beneficial agent 15 ceases when thedispensing element 150 and the structural members 12 of the prosthesisare not in alignment. To this end, the method can include a detectingstep to determine when the dispensing element 150 is aligned with thestructural members 12 of a prosthesis 10. The detecting step can beachieved by a sensor 160 such as an optical detector, e.g., linear arraydetector or infrared detector, ultrasound probe, temperature probe,camera, capacitance meter, electrometer, hall-effect probe, and thelike. However, any sensor 160 known in the art for detection is withinthe scope of the invention. Alternatively, a controller 170 may beprovided that is programmed with the structural member locations of apredetermined portion of the prosthesis to be loaded with beneficialagent. In this manner, the dispensing step is performed by thedispensing element as operated by the programmed controller. Theseaspects of the invention reduce or eliminate webbing and bridging ofbeneficial agent across openings or gaps within the structure of theprosthesis and minimizes waste. Furthermore, the dispensing element 150can be aligned such that the controlled trajectory of each droplet isdirected normal to the surface of the prosthesis, or at an anglethereto. Similarly, the trajectory path can be aligned to cross thecentral axis of the prosthesis, or be aligned off-axis thereto.

[0096] According to another aspect of the invention, the method ofloading beneficial agent onto the prosthesis includes providing aprosthesis including a tubular member having a central axis definedalong a length of the tubular member. This method further includesdispensing beneficial agent from a dispensing element capable ofdispensing beneficial agent in discrete droplets and in a controlledtrajectory to a surface of the prosthesis, wherein the controlledtrajectory of beneficial agent is aligned so as not to intersect thecentral axis of the tubular member.

[0097] For example, and for purpose of illustration and not limitation,FIGS. 8a-8 d depict various cross-sections of the interventional device10 of FIG. 6. In each cross-sectional view, the trajectory path 152 ofthe discrete droplets 155 is aligned “off-axis” so as not to passthrough the central axis 11 of the tubular member. Particularly, and asdepicted in FIGS. 8a through 8 d for purpose of illustration and notlimitation, the trajectory path 152 of the discrete droplets 155 isaligned tangentially between an inner surface and an outer surface ofthe tubular wall of the prosthesis 10. In this manner, likelihood ofimpact of a discrete droplet 155 of beneficial agent 15 with a surfaceof the prosthesis 10 is enhanced. If desired, however, alternativeoff-axis trajectory path alignment can be used in accordance with theinvention.

[0098] With reference to FIGS. 8a-8 d, the prosthesis provided by theprosthesis providing step includes a tubular member having a pluralityof interconnected structural members 12 defining openings 14therebetween, and further wherein the controlled trajectory 152 of eachdroplet is substantially tangential to a wall or surface of thestructural members 12 within the predetermined portion of theprosthesis. In this regard, the controlled trajectory 152 of beneficialagent 15 dispensed from the dispensing element 150 is aligned such thatit does not intersect the central axis of the prosthesis. This processallows for greater coverage of the structural elements, withoutrequiring selective operation of the dispensing element, if desired.That is, use of the “off-axis” approach allows for enhanced loading ofbeneficial agent on the prosthesis without selective or with onlylimited control of the dispensing element if desired. In a preferredembodiment, however, the dispensing element is at least controlled toterminate dispensing when the trajectory path is not aligned with thesolid profile of the predetermined area to be loaded, e.g. axiallybeyond either end 13 of the prosthesis 10, shown in FIG. 6. Inparticular, the dispensing element is turned “on” only when thetrajectory path of beneficial agent will intersect the solid area sweptout by 360 degrees rotation of the prosthesis. The dispensing element isturned off when the trajectory path of beneficial agent would notintersect or will miss the solid area and volume swept out by 360degrees rotation of the prosthesis.

[0099] Alternatively, and in accordance with a preferred embodiment ofthe invention, the “off-axis” method is performed using the rastertechnique previously described. That is, with the trajectory path 152aligned off-axis from the central axis of the prosthesis 10, such asshown in FIGS. 8a-8 d, discrete droplets can be selectively dispensedfrom the dispensing element 150 only when aligned with a structuralmember 12 of the prosthesis 10. In this embodiment, the relative motionof the dispensing element 150 and the prosthesis 10 define a dispensingpath which includes a sequential series of linear parallel passes thattraverse back and forth along one axis of the prosthesis. The relativemotion alternates between forward and backward, right to left, left toright, or upward and downward, depending on the frame of reference. Atraversal or pass is completed when the relative motion changesdirection. That is, relative motion continues past the prosthesis andthen decelerates, stops, reversed direction and accelerates to aconstant velocity. After each pass, the position of the dispensingelement 150 is changed or incremented such that additional drops ofbeneficial agent do not impact the same location as the previouslydispensed droplets during the subsequent pass. Any degree of overlap maybe permitted to achieve a desired areal density of beneficial agent.

[0100] Alternatively, the relative motion of the dispensing element andthe prosthesis define a dispensing path which includes a singlecontinuous helix that wraps around the prosthesis and along its length.The relative motion consists of continuously rotating, for example, theprosthesis and then incrementally advancing the dispensing element 150axially along the prosthesis. Both axial and radial motion preferablybegin before the item is aligned with the dispensing element to receivedroplets of beneficial agent, so as to enable acceleration of both axesto a constant velocity, and continues beyond the prosthesis where bothmovements may decelerate, and stop. After each rotation, the position ofthe dispensing element or prosthesis relative to the dispensing elementis moved or incremented axially such that additional droplets preferablydo not impact in the same location. However, any degree of overlap maybe permitted to achieve a desired areal density of beneficial agent.

[0101] The linear velocity during dispensing of droplets of beneficialagent can be constant or can be varied in a controlled way. Further, thepreferable position of the droplet trajectory is such that the dropletsinteract with the structural surfaces of the prosthesis at or near thetangent to its curved solid surface.

[0102] In a preferred embodiment the dispensing path 154 includes aseries of parallel passes along a surface of the prosthesis. For exampleand not limitation, the prosthesis provided can have a tubular bodyprior to its deployment in a lumen, and each parallel pass of thedispensing path 154 is parallel to the longitudinal axis 11 of theprosthesis 10 as shown in FIG. 6a. After each pass, the position of thedispensing element 150 or prosthesis 10 is changed or incremented sothat the discrete droplets 155 of beneficial agent 15 are dispensed ontoa surface of the prosthesis 10 that has not already been loaded.Alternatively, and as previously noted, the parallel passes can define ahelical pattern around the longitudinal axis of the stent, wherein eachpass is a complete turn of the helical pattern. For purposes ofillustration and not limitation, the relative motion of the dispensingelement and the prosthesis can include continuously rotating theprosthesis and incrementally advancing the dispensing element axiallyalong the length of the prosthesis. Preferably, after each rotation ofthe prosthesis, the position of the dispensing element is incrementallychanged axially such that additional droplets of beneficial agent thatare dispensed from the dispensing element load a surface of theprosthesis not already loaded by a prior pass. In an alternative aspectof the invention, the prosthesis can have a planar body prior loading,such that no rotation of the planar member is required for loading ofbeneficial agent thereon. The step of dispensing the beneficial agentonto the prosthesis along the dispensing path can be repeated to providemultiple passes along a predetermined portion of the prosthesis.

[0103] As noted above, the beneficial agent is selectively dispensedfrom the dispensing element along the dispensing path in a rasterformat. In this manner, the raster format can be achieved by turning thedispensing element on and off at predetermined intervals in response toa detector. Alternatively, the beneficial agent can be selectivelydispensed in a raster format by programming a controller device thatcommunicates with the dispensing element to dispense the beneficialagent according to the programmed data. A variety of fluid dispensersare available and suitable for providing discrete droplets along acontrolled trajectory. For example, a suitable drop-on-demand jettingsystem can be used, as shown in FIGS. 9 and 11, wherein discretedroplets are selectively dispensed from a jetting head. In this manner,the jet stream of discrete droplets can be turned on and off on demand,and the flow rate of discrete droplets can be increased or decreased asdesired. Alternatively, if a charge-and-deflect device is used, then acontinuous stream of droplets will be generated, and selected dropletswill be deflected as is known in the art, such as shown in FIG. 7, asdescribed further below.

[0104] In one preferred embodiment of the invention the prosthesis is astent, and as mentioned above, the fluid-dispenser is a fluid-jettingdevice. In accordance with the preferred embodiment, a driver 120continually advances the stent longitudinally along its axis at aconstant rate, to define a series of generally parallel passes 154 alongthe longitudinal axis 11 of the stent 10. The stent is the incrementallyrotated about its axis at the end of each pass. The stent is rotated atabout 1° to about 20° about its longitudinal axis, increments, andpreferably is rotated at about 5° increments.

[0105] The fluid-jetting head is turned on to provide droplets ofbeneficial agent whenever a stent strut or structural member is detectedimmediately in front of the jetting head, or based on a predeterminedprogrammed pattern that corresponds to the stent design, as mentionedabove. By further providing controlled flow rate dispensed from thejetting head, the beneficial agent can be provided in a rastered formatto confer the stent with a known quantity of beneficial agent. Ifdesired, the known quantity of beneficial agent is dispensed to providea uniform local areal density based on changes in surface area. As usedherein “local areal density” refers to the amount of beneficial agentper unit surface area of the stent or prosthesis.

[0106] For example and not limitation, a unit length of two differentstruts having different strut widths could each be loaded with an equalamount of beneficial agent by adjusting flow rate accordingly.Contrastly, the flow rate of the jetting head can be controlled alongthe progression of the stent to provide a first portion 10 b of theprosthesis 10 with a greater local areal density and a second portion 10a of the prosthesis with a lower local areal density, such as shown inFIG. 1. Similarly, the rate of relative movement between the jettinghead and the prosthesis can be varied to control local areal densityaccordingly.

[0107] As noted above, the dispensing path 154 is defined by therelative movement between the dispensing element and the prosthesis. Therelative movement between the dispensing element and the prosthesis maybe performed at a substantially constant velocity, or alternatively at avaried velocity to alter local areal density of beneficial agent, orintermittently. For an example of varied velocity, and with reference tothe embodiment of FIG. 1a for purpose of illustration and notlimitation, the linear travel speed of the prosthesis under the fluiddispenser is performed 50% faster during loading of beneficial agent onthe proximal and distal portions 10a and 10 c of the prosthesis body todecrease local areal density accordingly. Alternatively, the lineartravel speed of the prosthesis under the fluid dispenser may be 50%slower during loading of beneficial agent on the mid region of theprosthesis body to increase local areal density thereat.

[0108] Alternatively, rather than using a raster format, a vectortechnique can be used wherein a first portion of the stent strut at oneend of the stent is positioned in front of the jetting head and thejetting head is turned on. The jetting head is then left on to dispensedroplets of beneficial agent at a constant predetermined frequency toprovide a predetermined dispensing rate of agent. The two-axis controlsystem, described further below, is directed to continuously move thestent, coordinating both axes simultaneously so that the predeterminedshape of the stent struts are advanced in front of the jetting head.This movement continuously places the beneficial agent on the struts ofthe first portion until the desired surface of the stent has beenpositioned to receive beneficial agent over the known surface area, anda predetermined quantity of beneficial agent has been dispensed. Thebeneficial agent is provided on the stent struts and the jetting headthereby does not disperse beneficial agent in areas wherein metal hasbeen removed from the stent. This process may be repeated for subsequentportions of the interventional device, such that known quantities ofbeneficial agent are provided over each corresponding portion of theinterventional device. As with the raster format, flow rate or rate ofrelative movement can be controlled to adjust local areal density ofbeneficial agent as desired.

[0109] In yet another embodiment, the two-axis positioning system iscoupled to a charge-and-deflect jetting head. A charge-and-deflectjetting head is capable of producing a rastered pattern of droplets overa predetermined width of the stent. That is, it is also in accordancewith the invention to apply a surface charge to selected droplets ofbeneficial agent dispensed from the dispensing element. Preferably, if apositive surface charge is applied to the beneficial agent, anantioxidant can be included in the beneficial agent. In this manner, theantioxidant can help to prevent the oxidation of a beneficial agent thatmight otherwise oxidize when positively charged. Additionally, oralternatively, other known techniques can be used to prevent or inhibitoxidation of beneficial agent. The trajectory of charged droplets ofbeneficial agent can be altered by a deflection field. For example, anelectrode 144 may be used to deflect the trajectory of beneficial agent,which is charged by a charger 142, towards a predetermined portion ofthe prosthesis as shown in FIG. 7. If desired, a charge opposite thatinduced on the droplets of beneficial agent can be applied to apredetermined portion of the prosthesis to provide an electrostaticattraction between the droplets of beneficial agent and the prosthesisfor greater accuracy and efficiency.

[0110] To effect predetermined loading of beneficial agent, or coatingthickness, several methods of controlling the two-axis positioningsystem in coordination with control of the fluid dispensing are possibleso as to result in a precise deposition of beneficial agent on the outersurface of the stent or prosthesis 10. First, the motor 122 thatcontrols rotation of the prosthesis about its longitudinal axis can beturned on to produce a constant angular velocity. A second motor 124 isthen controlled to advance the prosthesis or stent in front of thedispensing element 150 at a predetermined rate to generally describe aspiral or helix across the longitudinal axis of the stent, where thepitch width, from rotation to rotation, is the same as the raster widthof the dispensing element 150. When a charge-and-deflect dispensingelement is used, the surface of the prosthesis 10 or stent can beexposed to the dispensing element 150 in a more rapid manner than forthe single drop wide raster pattern that is possible with thedrop-on-demand mode system. When the first stent strut is detected to bepresent in front of the jet head 150, a bit-mapped pattern that has beenpreviously stored in memory 170 to describe the shape of the struts israstered out by providing appropriate charges on selected droplets.Second, a linear array detector 160 with resolution similar to thenumber of droplets in each raster line can detect, by reflected ortransmitted light, the presence of a stent strut that is about torevolve in front of the jetted fluid window. The data from this type ofdetector can then be transferred to a shift register which produces thenecessary raster data by shifting the bit pattern out a bit at a time.With this method, no predetermined bit-map is necessary, and any slightvariations in speed, edge detection or position may be automaticallycompensated. This process may be repeated for subsequent portions of theinterventional device, such that known quantities of beneficial agentare provided over each corresponding portion of the interventionaldevice.

[0111] Further in accordance with the invention, a system for loadingbeneficial agent onto a prosthesis for delivery within a lumen isprovided. As shown in FIG. 7 and FIG. 13, the system includes a holder110 for supporting a prosthesis and a fluid-dispenser having adispensing element 150 capable of dispensing beneficial agent 15 indiscrete droplets 155, each droplet having a controlled trajectory.

[0112] The holder includes a mandrel or spindle 112 made of any suitablematerial known in the art. Preferably, however, the spindle 112comprises a superelastic material, such as nitinol, or any othermaterial that has shape memory properties. Particularly, manipulation ofa stent holder made of stainless steel can result in bending anddeformation of the spindle. Such deformation causes poor rotationalaccuracy and high run-out, e.g., 0.25-2.5 mm, from one end of thespindle to the other end of the spindle. This can cause a lowerefficiency of loading beneficial agent onto a prosthesis, and lowerefficiency of droplet interaction with the prosthesis because theposition of the stent under the jetting head varies as the run outvaries. Superelastic materials generally have properties that are ableto absorb and recover from up to 8% strain force. Thus, advantageously,nitinol provides a more resilient spindle capable of undergoing repeatedmanual stent mounting without the plastic deformation that occurs with astainless steel spindle design.

[0113] For purpose of illustration and not limitation, and as shown inFIG. 13, a nitinol spindle 112 may be made using a centerless grindingtechnique to obtain high concentric accuracy. Despite this grindingprocess, the centerline of the small diameter part of the spindle (e.g.,0.5 mm diameter) can vary a few degrees from the centerline of theintermediate diameter section (e.g., 2 mm diameter). This variance canbe removed by heating the spindle near the junction of the small andintermediate diameter section and bending it to remove most of theresidual run out. Upon cooling, the spindle, shown in FIG. 13, assemblyretains its new position. The final run out on an exemplary spindleafter using these techniques was about 0.051 mm.

[0114] The system also includes a driver such as a driver assembly 120to create relative movement between the holder 110 and the dispensingelement 150, and a controller 170 in communication with the driver 120to define a dispensing path of relative movement between the dispensingelement 150 and the holder 110. The controller also communicates withthe dispensing element 150 for selectively dispensing beneficial agentin a selected format along the dispensing path onto a selected portionof the prosthesis 10 supported by the holder 110. In one aspect of theinvention the holder 110 supporting the prosthesis 10 is moveable whilethe dispensing element 150 remains stationary during dispensing ofbeneficial agent 15. However, in another aspect of the invention theholder 110 supporting the prosthesis 10 remains stationary while thedispensing element 150 moves along the dispensing path. Alternatively,both the holder 110 and dispensing element 150 are moveable. In anotheraspect of the embodiment, as previously described, the system includes adetector 160 to detect when the dispensing element 150 is aligned withthe predetermined portion of the prosthesis 10. Various known componentscan be used in combination for construction of the system of the presentinvention. For example, jetLab System II from MicroFab Technologies ofPlano, Tex., as modified to include the desired features of theinvention can be used.

[0115] In yet another embodiment of the invention, a determination ofthe quantity of beneficial agent dispensed over a given or known surfacearea can be established. According to one aspect, a predetermined ratioof an identifiable marker is added to the beneficial agent and both thebeneficial agent and the marker are loaded onto the prosthesis.Subsequently, the amount of identifiable marker loaded onto theprosthesis is detected to determine the amount of correspondingbeneficial agent loaded onto the prosthesis. In one aspect of theinvention, the identifiable marker includes radiopaque material. Afterloading the radiopaque material with the beneficial agent onto theprosthesis, the prosthesis is imaged and an intensity value is measuredto determine the amount of beneficial agent loaded thereon and thuslocal areal density. The identifiable marker in this aspect can alsoinclude a fluorescent dye, e.g., coumarin dye. In another aspect of theinvention, the identifiable marker includes charged particles, forexample and not limitation, protons or electrons. After loading themarker and beneficial agent onto the prosthesis the detecting stepincludes measuring a charge build-up on or current flow from theprosthesis resulting from the charged particles. The charge build-up orcurrent flow therefore generally corresponds to the amount of beneficialagent loaded onto the prosthesis. Alternatively, because the fluidjetting technology of the present invention is inherently digital, thequantity of beneficial agent dispensed can be determined by counting thedroplets that have been jetted or dispersed.

[0116] In yet another alternative, the amount of beneficial agent loadedcan be measured more generally by weighing the stent before the jettingoperation and then after the jetting operation. The weight differencecorresponds to the drug loaded with the concentration being a functionof the jet flow rate along the length of the stent. Yet another methodis to integrate the charge build-up on the prosthesis when acharge-and-deflect system is used. Since each droplet in acharge-and-deflect jetting system has had a surface charge injected ontoit to enable the droplet to be deflected in an electrostatic field,either the loss of charge at the charging electrode or the accumulationof charge on the prosthesis can be integrated over time to determine thetotal volume of fluid that has accumulated on the surface of the device.

[0117] Also in accordance with the invention, an on-board spectrometermay be utilized for monitoring the beneficial agent concentration on thejetter reservoirs as a function of time. It is desirable to loadbeneficial agent such as a drug at a constant concentration. However,due to the evaporation of solvent during the loading process, theconcentration of drug will increase. Advantageously, a spectrometer canbe configured with a pump to add solvent to the drug such that aconstant absorbance on the spectrometer is maintained. The constantabsorbance level of the spectrometer is pre-set to monitor anappropriate wavelength. The maintenance of a constant absorbance readingon the spectrometer by the addition of solvent translates to themaintenance of a pre-set drug concentration.

[0118] For drop-on-demand jetting systems, this same drug quantificationconcept can be utilized by adding a constant voltage charging electrodeadjacent to the nozzle of the dispenser so as to add a polar charge toeach droplet. The coating on the stent, if an insulator, will act as acapacitor to the charge. This detection technique will be able to detectcharge build up if a small leakage path is provided or if a secondreference surface is provided against which to compare charge build up.Other alternative techniques can be used. For example, if a metalmandrel is present inside the stent it may be used to monitor any lostdroplet or splash. The charge that directly transfers to this“electrode” will create an opposite polarity current to the chargepresented to the insulated coated surface of the stent.

[0119] For each of these detection techniques described above, anappropriate detector can be incorporated in the system of FIG. 7,preferably in communication with controller 170.

[0120] In accordance with another aspect of the invention, a secondbeneficial agent or multiple beneficial agents can be loaded onto theprosthesis as described above. Therefore, further in accordance with theinvention, an interventional device comprising a prosthesis loaded witha plurality of discrete droplets of a first beneficial agent and aplurality of discrete droplets of a second beneficial agent is provided,such as by using the system and method shown in FIG. 9.

[0121] Particularly, the method described in detail above for onebeneficial agent can be modified to allow for loading multiplebeneficial agents onto a prosthesis, which might ordinarily lead toundesirable results when using conventional loading techniques. Forexample and not limitation, the first beneficial agent and the secondbeneficial agent may have different physical and/or chemicalcharacteristics preventing the beneficial agents from being capable ofdissolving in the same solvent, or at the same pH or temperature. Inparticular, the first beneficial agent can be dissolved in a solventthat is immiscible with the solvent in which the second beneficial agentis dissolved. Alternatively, the first beneficial agent and the secondbeneficial agent may be incompatible with each other. In particular, thefirst beneficial agent and the second beneficial agent can beundesirably chemically reactive or may have undesirably differentrelease rates (or contrarily, undesirably similar release rates).Additionally, the first and second beneficial agents can simply bedetrimental to each other, e.g., one of the beneficial agents maydegrade the efficacy of the other beneficial agent. Thus, althoughloading the particular multiple beneficial agents onto the same surfaceof a prosthesis can be desired it often may be problematic due to someincompatibility when using a conventional loading technique. Inaccordance with the present invention, a method of loading suchbeneficial agents and an interventional device for the delivery of suchbeneficial agents is provided.

[0122] As noted above, the beneficial agents are loaded in a pluralityof discrete droplets on the surface of the prosthesis. The discretedroplets of multiple beneficial agents are preferably loaded onto theprosthesis as unmixed droplets to provide an interspersed pattern oralternatively, the unmixed droplets of beneficial agent can be loadedonto the prosthesis to provide an overlapping pattern of the firstbeneficial agent and the second beneficial agent. In this manner, theedges of the droplets overlap or alternatively, a larger surface of thedroplet overlaps other droplets to provide a layering effect, asdepicted in FIG. 10.

[0123] Multiple fluid-dispensers preferably are in accordance with theinvention, wherein each beneficial agent to be loaded onto theprosthesis is dispensed from a distinct dispensing device. For purposeof illustration and not limitation as shown in FIG. 9, a first dispenser150 is provided with a first beneficial agent 15′ dissolved in a solventthat is compatible for that particular first beneficial agent. Further,a second fluid-dispenser 150″ is provided with a second beneficial agent15″ that is different from the first beneficial agent 15′, and requiringa different solvent for compatibility. For example, the first beneficialagent could be a water-soluble agent, whereas the second beneficialagent could be a water-insoluble agent, each requiring a differentsolvent. Accordingly, both beneficial agents are loaded onto the samesurface of the prosthesis without problems arising from theirimmiscibility.

[0124] Where two fluid-dispensers are used to load the multiplebeneficial agents onto the prosthesis, the trajectories of discretedroplets corresponding to each of the first beneficial agent and thesecond beneficial agent can be aligned such that the droplets from eachbeneficial agent combine and mix prior to their being loaded on theprosthesis. In this manner, the first and second beneficial agent canform a third beneficial agent which is loaded onto the prosthesis. Forpurpose of illustration and not limitation, the first beneficial agentmay be bisphenol-A-diglycidyl ether and the second beneficial agent canbe triethylenetetramine. Upon combination of the first beneficial agentand the second beneficial agent, a cross linked coating is formed toprovide a third beneficial agent. In yet another illustrative example,the first beneficial agent can be bisphenol-A-diglycidyl ether andpaclitaxel and the second beneficial agent can be triethylenetetramine.Upon the combination of the two controlled trajectories of beneficialagents, a third beneficial agent is formed, a cross-linked coatingentrapping paclitaxel, which is loaded on the prosthesis. Alternatively,the discrete droplets of the first and second beneficial agent can bealigned along trajectories to mix on the surface of the prosthesis.

[0125] As noted above, the beneficial agent can include a drug andpolymer mixture. In accordance with the method of the invention, thefirst and second beneficial agents can correspond to drug-polymermixtures having different concentrations of polymer to effect differentrelease rates of the particular drug in each beneficial agent. Forexample, the drug-polymer mixture having a higher concentration ofpolymer would have a slower release of the drug within the lumen than adrug-polymer mixture having a lower concentration. Alternatively, ratherthan providing drug-polymer mixtures having different polymerconcentrations to provide different release rates, it is also possibleto dispense beneficial agents using different polymers or other binders,wherein the specific polymer or binder has different diffusivity oraffinity to assure delivery of the beneficial agents at different rates.Thus, in accordance with the invention, multiple beneficial agents canbe released at rates appropriate for their activities, such that theprosthesis of the invention has multiple beneficial agents which eluteoff the prosthesis at desired rates.

[0126] For example, a cationic phosphorylcholine-linked polymer whichhas a higher affinity for anionic therapeutic agents can be blended anddispersed as a first beneficial agent and lipophilicphosphorylcholine-linked polymer can be blended with lipophilic drugs asthe second beneficial agent to effect different release ratesrespectively.

[0127] In yet another embodiment of the invention, one of the first andsecond beneficial agents loaded onto the prosthesis can be morehydrophobic or less water-soluble than the other. Thus, in accordancewith the invention is provided a prosthesis including first and secondbeneficial agents wherein one of the beneficial agents is morehydrophobic or less water soluble than the other. In this manner, themore hydrophobic beneficial agent acts as a water barrier or hydrationinhibitor for the less hydrophobic beneficial agent, thereby reducingthe release rate of the less hydrophobic beneficial agent as disclosedin U.S. Provisional Patent Application 60/453,555 and PCT/US03/07383,each of which was filed on Mar. 10, 2003, and each of which isincorporated herein by reference thereto.

[0128] In addition to providing a prosthesis having multiple beneficialagents which are delivered at unique or desired rates, according toanother aspect of the invention, the first beneficial agent can bedissolved in solvent wherein the second beneficial agent causes thefirst beneficial agent to precipitate out of the solvent. For exampleand not limitation, the first beneficial agent may be rapamycindissolved in ethanol, and the second beneficial agent may be water. Upondroplet combination using the method and system of the invention, therapamycin will precipitate within the droplet and be deposited on theprosthesis as a microprecipitate.

[0129] In yet another aspect of the invention, at least one of the firstand second beneficial agents can be mixed with a binder prior to beingloaded onto the prosthesis. Further in accordance with this aspect oneof the beneficial agents can be a curative agent for curing the binderon the prosthesis with the beneficial agent mixed therein. For example,see Example 4 below.

[0130] As noted above, one of the beneficial agents can be a solvent forthe other beneficial agent. Thus, in accordance with the invention, thefirst beneficial agent, e.g., a drug, polymer, or a combination thereof,can be loaded onto the prosthesis, and subsequently the secondbeneficial agent, i.e., a solvent, can be loaded onto the prosthesis soas to redistribute the first beneficial agent more uniformly along theprosthesis.

[0131] As also noted above, the prosthesis can include at least onereservoir or cavity or trough therein. For purpose of illustration andnot limitation, computer controlled profiles of a laser cut stent can beutilized to precisely deposit beneficial agent into the laser cuts onthe stent struts. For example, a longitudinal trough can be laser cut,etched, or otherwise formed into the strut, such as in the curve or bendof the strut for instance. In accordance with a preferred aspect of theinvention, the cavity or trough is provided with a contouredcross-sectional profile for retention and elution of beneficial agenttherein. Particularly, and as depicted schematically in FIG. 12, thecross-sectional profile of the cavity or trough 16 includes a smallerdimension at the interface with the strut surface, so as to define amouth 17 of the trough 16, and a larger internal cross-dimension of thetrough to define a reservoir 18. FIG. 12 shows one such embodiment,wherein mouth 17 is defined for reservoir 18 of trough 16. Use of thefluid jet system and method of the present invention thus allows forbeneficial agent to be loaded into the mouth 17 of trough 16, withoutthe entrapment of air within the reservoir 18. An appropriate volume ofbeneficial agent is deposited in the laser cut profile to at leastpartially fill the reservoir 18. In this respect, beneficial agent thatis deposited in the longitudinal trough can include a combination ofdrugs or a combination of polymers or a combination of drugs andpolymers in different layers. Furthermore, different layers of polymerand/or drug having different concentrations, or different drug elutionrates can be loaded therein. Additionally, an interim polymer and/orfinal polymer overcoat can be applied over the beneficial agent. Such adeposition configuration in combination with cavities is particularlybeneficial for minimizing delamination of the polymer-drug layers, andalso provides versatility in controlling drug elution and the generationof various combinations of drug release patterns. A computer profilingapproach is also useful to coat drug and polymer layers on the distaland proximal edges of the stent.

[0132] In accordance with another aspect of the invention, one or moreof the reservoirs or cavities or troughs is loaded with a morehydrophilic first beneficial agent and then a second more hydrophobicbeneficial agent is loaded onto the first beneficial agent within thecavity or reservoir in a manner as described above.

[0133] Further in accordance with the invention, using the method andsystems described above, a first beneficial agent loaded onto theprosthesis can have a first local areal density and a second beneficialagent loaded onto the prosthesis can have a second local areal density.As used herein, “areal density” refers to the amount of beneficial agentper unit surface area of a selected portion of the prosthesis. “Localareal density” refers to the dosage of beneficial agent per localsurface area of the prosthesis. The local areal density of the firstbeneficial agent and the local areal density of the second beneficialagent can be uniform across each respective portion to define steppedchanges in local area density as depicted in FIG. 1b or can be variedacross a selected portion of the prosthesis to define gradients of localarea density, as depicted in FIG. 1c. Accordingly, an interventionaldevice is provided having a prosthesis that is at least partially loadedwith beneficial agent having a local areal density that is varied alonga selected portion of the body of the prosthesis.

[0134] In accordance with a preferred embodiment, the prosthesis has atubular body when deployed in a lumen. Preferably, the tubular bodyincludes a first and second portion at least partially loaded withbeneficial agent such that the first portion has a first local arealdensity and the second portion has a second local areal density. Eachportion may be defined as a preselected length of the prosthesis.Alternatively, as shown in FIG. 1b, the first portion can be defined bya selected set of interconnected structural members and the secondportion can be defined as a second set of interconnected members e.g.,connectors elements or ring-elements. For example and not limitation, atleast one of the first and second set of selected interconnectedelements can define at least one ring-shaped element extending aroundthe circumference of the prosthesis.

[0135] In another embodiment of the invention, the local areal densityis varied as a continuous gradient along a selected portion of theprosthesis as shown in FIG. 1c. Accordingly, in one aspect of theinvention the local areal density of beneficial agent is varied such asto provide a prosthesis having a local areal density of beneficial agentat the ends of the prosthesis that is different than the local arealdensity of beneficial agent at an intermediate section of theprosthesis. For purpose of illustration and not limitation, the localareal density of beneficial agent at the intermediate section of theprosthesis can be greater than that at the proximal and distal ends ofthe prosthesis as shown in FIG. 1c. Alternatively, the proximal anddistal ends of the prosthesis can have a greater local areal density ofbeneficial agent than that on the intermediate section of theprosthesis. In a preferred embodiment of the invention, the varied localareal density of beneficial agent corresponds to the location of alesion when the prosthesis is deployed within a lumen. For example, theprosthesis can be loaded to have a greater local areal density ofbeneficial agent along a preselected portion of the prosthesis thatcorresponds to the location of the lesion when the prosthesis isdeployed in a lumen. Thus, targeted therapy may be achieved with theinterventional device of the present invention.

[0136] In accordance with the invention, the local areal density can bevaried by varying the relative rate in which beneficial agent is loadedto a selected location along the prosthesis. To this end, the frequencyin which the droplets of beneficial agent are applied along a unitlength of the dispensing path to the prosthesis is varied.Alternatively, the relative rate of loading beneficial agent can bevaried by varying the relative movement between the dispensing elementand the prosthesis. Another alternative for varying the relative rate ofloading beneficial agent is to vary the amount of beneficial agent perdroplet dispensed from the dispensing element. Other alternatives forvarying the local areal density of beneficial agent loaded onto theprosthesis include mixing the beneficial agent with a binder and varyingthe ratio of beneficial agent to binder. Alternatively, the amount ofthe mixture of beneficial agent and binder that is applied to theprosthesis can be varied to achieve a varied local areal density ofbeneficial agent. Other methods of varying the local areal density ofbeneficial agent known in the art may be used.

[0137] As noted above, the beneficial agent is at least partially loadedonto a surface of the prosthesis. Further in accordance with theinvention the prosthesis includes a first surface and a second surfacethat are at least partially loaded with beneficial agent. In oneembodiment of the invention, the first surface and the second surfaceeach correspond to one of the inner surface and the outer surface of theprosthesis. Thus, according to this particular embodiment, beneficialagent, as defined above, is loaded onto the inner or luminal surface ofa prosthesis as well as the outer surface of the prosthesis. The methoddescribed above can be used for this aspect of the invention, whereinthe beneficial agent is loaded on the inner surface of the prosthesis byinserting a fluid dispensing element within the inner diameter of theprosthesis, or by dispensing beneficial agent 15 diametrically acrossthe prosthesis 10 between structural members 12 to impact the innersurface on the opposite side of the prosthesis 10 as shown in FIG. 11.In this regard, the dispensing element 150″ is aligned so that thecontrolled trajectory 152″ of discrete droplets 155″ of beneficial agentoptimally intersect with the inner surfaces of the structural featuresof the prosthesis 10 and not intersect with the structural features ofthe outer surface of the prosthesis. For purposes of illustration andnot limitation, for a prosthesis comprising an odd number of radialrepeats in the pattern of structural features, the preferred alignmentof the dispensing element is orthogonal to the central axis of theprosthesis and in a plane that intersects the central axis of theprosthesis. However, for a prosthesis comprising an even number ofradial repeats in the pattern of structural features, the preferredalignment of the dispensing element to the prosthesis is orthogonal tothe central axis of the prosthesis, but in a plane that does notintersect the central axis of the prosthesis. As another example, for aprosthesis including a tubular member comprising multiple radially andaxially repeating structural elements, the preferred alignment of thedispensing element can be determined by assessing the shadow cast by theforeground or outer structural elements on the background or innerstructural elements. The preferred plane to align the dispensing elementcan be determined by assessing the plane in which the maximum amount ofunobstructed inner surface is presented upon rotation of the tubularmember.

[0138] In accordance with this aspect of the invention, the relativemotion of the dispensing element and the prosthesis can be coordinatedto enable a preprogrammed “raster” image of the position or locations ofthe structural elements of the inner surface. Alternatively, the vectorpattern of the structural elements may be preprogrammed, as previouslydescribed. Also, in accordance with the invention, the beneficial agentis dispensed from the dispensing element along a controlled trajectorythat is substantially tangential to or near the outer surface of theprosthesis and is loaded on the inner surface of the structural elementsof the prosthesis.

[0139] In this aspect of the invention, the interventional device can bedesigned to provide combination therapy of beneficial agents to targetedlocations. For example and not limitation, the particular beneficialagent loaded to the luminal or inner surface of the prosthesis can beintended for systemic release, whereas the particular beneficial agentloaded onto the outer surface of the prosthesis is intended for releaseinto the wall of the lumen. In accordance with one aspect of theinvention, the beneficial agents loaded onto the luminal side or innersurface of the prosthesis include, without limitation, antiplateletagents, aspirin, cell adhesion promoters, agents that promoteendothelial recovery, agents that promote migration, and estradiol. Thebeneficial agents loaded onto the outer surface of the prosthesisinclude without limitation, anti-inflammatories, anti-proliferatives,smooth muscle inhibitors, cell adhesion promoters, and the rapamycinanalog ABT-578, i.e.,3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Hexadecahydro-9,27-dihydroxy-3-[(1R)-2-[(1S,3R,4R)-3-methoxy-4-tetrazol-1-yl)cyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone;23,27-Epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone.

[0140] In accordance with another embodiment of the invention, the firstsurface of the prosthesis is defined by a plurality of interconnectingstructural members. Accordingly, the first surface can include a firstselected set of structural members, e.g., a connector member, and thesecond surface can include a second selected set of the structuralmembers, e.g., a ring-shaped element extending around the circumferenceof the prosthesis.

[0141] As noted above, the beneficial agent is loaded onto theprosthesis to provide a controlled local areal density across a lengthof the interventional device. That is, it may be desirable to provide agreater concentration of beneficial agent at one portion of a prosthesisand a lower concentration, or perhaps no beneficial agent, at anotherportion of the prosthesis. For example, in one preferred embodiment, agreater local areal density can be provided at a first portion, e.g.,intermediate portion 10 b, of a stent 10, as shown in FIG. 1a, whileproviding a lower local areal density of beneficial agent to a secondportion, e.g., one or both end portions (10 a, 10 c), of the stent 10.In accordance with the present invention, each of the first and secondportions of the prosthesis may be defined by any of a variety ofpatterns or selected portions of the prosthesis. For example, the firstportion of the prosthesis can be defined by longitudinal connectorswhereas the second portion of the stent is defined by annular rings, orvice versa, as illustrated in FIG. 6.

[0142] In accordance with another aspect of the present invention, theinterventional device includes a first prosthesis and a secondprosthesis in combination to define an overlapping portion and at leastone non-overlapping portion. For example, and as embodied herein, FIGS.2 or 3 present a schematic representation of a nested interventionaldevice including a first prosthesis 20 and a second prosthesis 30configured to be deployed in an overlapping relationship. Theinterventional device, however, can optionally include more than twoprostheses in combination, if desired. Such interventional devices 50include but are not limited to nested stents and modular bifurcatedstents. For purpose of illustration and not limitation, FIG. 2 shows afirst prosthesis 20 having a first portion 20 a and a second portion 20b and a second prosthesis 30 having a first portion 30 a and a secondportion 30 b. As shown schematically, the beneficial agent distributionprofile includes a first local areal density of beneficial agent on oneof the first and second portions of one or both of the first prosthesisand the second prosthesis. For example and not by limitation, the firstportion 20 a of the first prosthesis 20 has half the local areal densityof beneficial agent as compared to the second portion 20 b of the firstprosthesis 20. The first portion 30 a of the second prosthesis 30,likewise, has half the local areal density of beneficial agent comparedto the second portion 30 b of the second prosthesis 30. In this manner,when the ends of two stents are superimposed or deployed in anoverlapping relationship 25 during a procedure, the local areal densityof beneficial agent along the interventional device 50 is controlled soas to be uniform. If desired, alternative concentrations can be providedon each portion so as to provide the desired effect in combination.

[0143] In accordance with the present invention, as shown in FIG. 3, acontrolled local areal density of beneficial agent is thus providedacross a length of the interventional device 50 upon combination of thefirst prosthesis having first portion 20 a and second portion 20 b withthe second prosthesis having first portion 30 a and second portion 30 b,as shown in FIG. 2. In particular, as shown in FIG. 3, the overlappingsegment 25 of first prosthesis 20 and the second prosthesis 30 has anequal local areal density of beneficial agent as compared tonon-overlapping segments 20 b and 30 b.

[0144] Alternatively, the beneficial agent distribution profile for theinterventional device may be controlled to include any of a variety ofdesired patterns. For example, the interventional device can have adecreased local areal density of beneficial agent on the distal andproximal ends of each prosthesis body, as noted above. This profile ishighly desirable in preventing adverse dosing of beneficial agent ifmultiple prostheses are placed in combination with each other but stillprovides for decreased dosage of the extreme ends of the interventionaldevice as a whole. Alternatively, as embodied herein, the beneficialagent distribution profile can provide a controlled local areal densitythat is uniform along the length of first prosthesis and secondprosthesis in combination, or multiple prostheses in combination.Alternatively, in accordance with the invention, the beneficial agentdistribution profile provides a controlled local areal density that isvaried along the length of the first prosthesis and the secondprosthesis in combination, or multiple prostheses in combination.

[0145] For illustration purposes, overlapping or nested prostheses, asshown in FIG. 3, can have beneficial agent distribution profiles suchthat the controlled local areal density of beneficial agent of anon-overlapping segment is in fact greater than the controlled localareal density of beneficial agent of a overlapping segment. Similarly,the alternative can also be true; that a overlapping segment iscontrolled to have a greater or different local areal density ofbeneficial agent than a non-overlapping segment. Advantageously, thisfeature also enables selective dosing of beneficial agent to a targetedarea when using multiple prostheses in combination, as well as a singleprosthesis alone. Selective dosing of beneficial agent to a targetedarea means that the beneficial agent can be applied to the prosthesis orprostheses in combination such that the desired beneficial agent isloaded onto the prosthesis in a selective pattern so that the beneficialagent or beneficial agents are released from the prosthesis in closeproximity to a targeted location. Fluid jetting as previously describedis particularly preferred for selective dosing.

[0146] In accordance with the present invention, and as embodiedschematically in FIG. 5, a bifurcated interventional device also can beprovided, which includes a first prosthesis 20′ and a second prosthesis30′ in combination to define an overlapping portion 50′ and nonoverlapping portions 20 b′, 30 b′. For purposes of illustration and notlimitation, FIG. 4 shows a first prosthesis 20′ having a first portion20 a′ and a second portion 20 b′, and a second prosthesis 30′ having afirst portion 30 a′ and a second portion 30 b′. As shown for purpose ofillustration and not limitation, the beneficial agent distributionprofile includes a first local areal density of beneficial agent on oneof the first and second portions of one or both of the first prosthesis20′ and the second prosthesis 30′. For example, and not by limitation,the first portion 20 a′ of the first prosthesis 20′ has half the localareal density of beneficial agent as compared to the second portion 20b′ of the first prosthesis. The first portion 30 a′ of the secondprosthesis 30′ has half the local areal density of the second portion 30b′ of the second prosthesis 30′. In accordance with the presentinvention, as shown in FIG. 5, a controlled local areal density ofbeneficial agent is thus provided across a length of the bifurcatedinterventional device 50 upon combination of the first prosthesis havingfirst portion 20 a′ and second portion 20 b′ with the second prosthesishaving first portion 30 a′ and second portion 30 b′, as shown in FIG. 4.

[0147] Another feature of the present invention includes applying alayer of base material on a selected portion of the prosthesis describedabove. The beneficial agent is loaded onto the base material layeraccording to the methods described above. The base material layerpreferably defines a pattern for loading the beneficial agent onto theprosthesis.

[0148] The present invention also encompasses, for any of theembodiments disclosed, the application of a rate-controlling topcoatover the beneficial agent loaded prosthesis for further controlling orsustaining the release of beneficial agent. The rate-controlling topcoatmay be added by applying a coating layer posited over the beneficialagent loaded prosthesis. The thickness of the layer is selected toprovide such control. Preferably, the overcoat is applied by fluid-jettechnology. Advantageously, fluid jetting an overcoat such as a polymerovercoat allows a thinner and more uniform layers. However otherconventional methods can be used such as other fluid-dispensers, vapordeposition, plasma deposition, spraying, or dipping, or any othercoating technique known in the art.

[0149] The present invention also provides a method for manufacturing aninterventional device for delivery of beneficial agent This methodcomprises the steps of providing a first prosthesis to be deployedwithin a lumen; providing a second prosthesis configured to be deployedin an overlapping relationship with the first prosthesis, the firstprosthesis and the second prosthesis in combination defining at leastone non-overlapping segment and an overlapping segment; and loading thefirst prosthesis and the second prosthesis with beneficial agent toprovide a controlled local areal density along a length of the firstprosthesis and the second prosthesis in combination. The methoddescribed in detail above is preferred for such loading step.

[0150] The present invention also provides a method of deliveringbeneficial agent. In accordance with this method, as described in detailin conjunction with the description of the interventional device of thepresent invention above, the method comprising the steps of providing afirst prosthesis having a tubular body when deployed in a lumen;providing a second prosthesis having a tubular body when deployed in alumen; loading at least one of the first prosthesis and the secondprosthesis with beneficial agent; deploying the first prosthesis into alumen; deploying the second prosthesis into the lumen to define incombination with the first prosthesis at least one non-overlappingsegment and an overlapping segment; wherein the beneficial agent isloaded onto at least one of the first prosthesis and the secondprosthesis to provide a controlled local areal density of beneficialagent across a length of the first prosthesis and the second prosthesiswhen deployed. The method described in detail above is preferred forsuch loading step.

[0151] The present invention will be further understood by the examplesset forth below, which are provided for purpose of illustration and notlimitation.

EXAMPLES Example 1

[0152] Jetting of Reactive Substances

[0153] The components of a commercial two-part epoxy formulation aremixed by the jetting process and applied to a surface to form a coating.In a formulation manufactured by Buehler, Lake Bluff Ill., one part is aliquid “epoxide resin” that contains 4,4′ isopropylidenediphenolepichlorohydrin resin and butyl glycidyl ether. The second part is aliquid “hardener” that contains diethylene triamine, triethylenetetramine, and polyoxypropylenediamine. In the jetting process, onereagent jet system (A) is loaded with epoxide resin and a second jettingsystem (B) is loaded with hardener The jets are aligned such that thedroplets emanating from each jet combine in midair and travel to thetarget device to form a crosslinked coating, after a curing time of 2-8hours. The volume of a droplet emanating from jet A is 5 times largerthan the volume of a droplet emanating from Jet B and the total numberof droplets dispensed from each jet are approximately equal.

Example 2

[0154] Jetting of Reactive Substances

[0155] The components of a commercial two-part epoxy formulation aremixed by the jetting process and applied to a surface to form a coating.In a two part commercial formulation manufactured by Buehler, Lake BluffIll., one part is a liquid “epoxide resin” which contains 4,4′isopropylidenediphenol epichlorohydrin resin and butyl glycidyl ether.The second part is a liquid “hardener” that contains diethylenetriamine, triethylene tetramine, and polyoxypropylenediamine. In thejetting process, one reagent jet system (A) is loaded with epoxide resinand a second jetting system (B) is loaded with hardener. The jets arealigned such that the droplets emanating from each jet combine in midairand travel to the target device to form a crosslinked coating, after acuring time of 2-8 hours. The volume of a droplet emanating from jet Ais 4 times larger than the volume of a droplet emanating from Jet B andthe total number of droplets dispensed from each jet are approximatelyequal. This coating cures at a faster rate than the coating described inexample 1.

Example 3

[0156] Jetting of Reactive Substances

[0157] The components of a commercial two-part epoxy formulation aremixed by the jetting process and applied to a surface to form a coating.In a two part commercial formulation manufactured by Buehler, Lake BluffIll., one part is a liquid “epoxide resin” which contains 4,4′isopropylidenediphenol epichlorohydrin resin and butyl glycidyl ether.The second part is a liquid “hardener” that contains diethylenetriamine, triethylene tetramine, and polyoxypropylenediamine. In thejetting process, one reagent jet system (A) is loaded with epoxide resinand a second jetting system (B) is loaded with hardener. The jets arealigned such that the droplets emanating from each jet combine in midairand travel to the target device to form a crosslinked coating, after acuring time of 2-8 hours. The volume of a droplet emanating from jet Ais approximately equal to the volume of a droplet emanating from Jet B,but the total number of droplets dispensed from jet A is 4 times morethan from jet B.

Example 4

[0158] Formation of a Crosslinked Network Containing Biologically ActiveAgents

[0159] One reagent jet system (A) is loaded with a liquid epoxide resinand a solubilized formulation of the drug, paclitaxel, 20% by weightwith respect to the epoxide resin. A second jetting system (B) is loadedwith hardener similar to that described in example 1 combined with anequal weight or less of a biocompatible polymer. One example of such aspecies is a phosphorylcholine linked polymer of the general formulapoly(MPC_(w):LMA_(x):HPMA_(y):TSMA_(z)), where MPC is2-methacryoyloxyrthylphosphorylcholine, LMA is lauryl methacrylate, HPMAis hydroxypropyl methacrylate and TSMA is trimethoxysilylpropylmethacrylate. This polymer is dissolved in a solvent such as chloroform.The jets are aligned such that the droplets from each jet combine inmidair and travel to the target device to form a crosslinked coatingentrapping the drug and polymer. The volume of a droplet emanating fromjet A is 5 times larger than the volume of a droplet emanating from jetB and the total number of droplets dispensed from each jet areapproximately equal. The coating is heated for 4 hours at 70 degrees C.to cause crosslinking of the phosphorylcholine-linked polymerpredominantly with itself by means of the trimethoxysilane groups, andsimultaneously accelerating the curing of the epoxide resin with thehardener.

Example 5

[0160] Formation of a Drug Microprecipate

[0161] One reagent jet system (A) is loaded with rapamycin dissolved inethanol. A second jetting system is loaded with water. The dropletvolume of one drop emanating from jet A is 50 nanoliters and the dropletvolume of one drop emanating from Jet B is 150 nanoliters. The jets arealigned such that the droplets from each jet combine in midair andtravel to the target device. During the droplet combination therapamycin will precipitate within the droplet and be deposited on thetarget surface as a microprecipitate.

Example 6

[0162] Loading of Drug onto a Polymer Base-Coated Coronary Stent

[0163] In a demonstration of feasibility, a stock jetting solution of 20mg/ml ABT-578+4 mg/ml phosphorylcholine-linked methacrylate polymer (PC)in isobutanol was prepared. A fluid jetting system manufactured byMicroFab Technologies of Plano, Tex. was programmed to jet 75 microgramsof drug evenly over a 1.4×11 mm OC BiodivYsio stent to obtain an arealdensity of 5 micrograms per linear mm. Jetting of 21,888 drops into avial containing 10 ml of isobutanol gave 77 micrograms of ABT-578 asdetermined spectrophotometrically at 278 nm. Under these conditions, 1drop was 170-180 picoliters and had a diameter between 67 and 70microns. The stent contained a base coating of phosphorylcholine-linkedmethacrylate polymer (PC). It was mounted on a fixture that included amandrel that provided for controlled rotation (θ) about a central axiscoaxial with the stent and a stage that provided for lateral movement(X) along the axis of the stent. The motion control was set up to rotatethe stent a total of 720 degrees. A view orthogonal to the axis of therotating stent showed two possible tangential off-axis positions,approximately 50 microns inside a point tangent to the outer surface ofthe stent, one on each side of the rotation centerline, that providedrelatively few instances where a jet trajectory would not impinge on atleast one stent structural element. One of these off-axis positions wasfirst selected to start the drug loading. A mandrel mounted stent waspositioned so that the trajectory of jetted droplets would impinge onthe stent struts at this “off-axis” location. The motion controller wasset up to move the stent axially in the X direction and began its motionat a position where the jet trajectory was off the end of the stent. Themotion controller ramped up to a predetermined velocity and turned onthe fluid jetting head as soon as motion along the X axis reachedconstant velocity and the end of the stent struts were in a positiondirectly under the jet head. Every time the stent passed completelyunder the jet head along this off-axis path in the X direction, themotion controller would then ramp down the velocity, stop and rotate thestent 5 degrees. The linear direction was reversed and the next pass wasmade. After 360 degrees was reached, (72 passes) the table wastranslated approximately a distance equal to the internal diameter ofthe stent (1 ID) to the other off-axis position and 72 more passes weremade for an additional rotation of 360 degrees. Each stent was thusjetted twice to obtain its drug loading.

[0164] Seven (7) stents were loaded with drug. Observation ofdrug-loaded stents under a stereomicroscope indicated that no webbingoccurred between stent struts and the surfaces were cosmetically smooth.The stents were subsequently extracted into isobutanol for measurementof the drug obtained and the results are shown below. Stent ABT-578(micrograms) 1 70 2 72 3 69 4 69 5 53 6 61 7 60

[0165] The average loading obtained was 65 micrograms. The calculatedcapture efficiency was 84% based on the number of counted droplets ofdrug dispensed.

Example 7

[0166] Loading of PC-Coated Peripheral Stents by Reagent Jetting

[0167] In a similar feasibility demonstration experiment, a fluidjetting system manufactured by MicroFab Technologies of Plano, Tex. wasprogrammed to dispense 59,904 drops, approximately 3× that used for the11 mm OC stent. These peripheral vascular stents (SFA) were 5×30 mm andwere mounted on a larger sized rotation fixture. The stent matrix wasmuch more open than seen on the OC coronary stent; however, good captureefficiency was obtained. stent ABT-578 (micrograms) 1 187 2 176 3 185average 183 Avg.

[0168] The jetter dispensed 211 micrograms of drug per stent, having acapture efficiency of 86%.

Example 8

[0169] Overcoating of a Drug-Loaded Stent with Polymer

[0170] A 10 mg/ml solution of phosphorylcholine-linked methacrylatepolymer (PC) was made in isobutanol. A total of 288 passes along theaxial dimension of the stent and over 1440 degrees of rotation under theconditions used in previous examples, produced an overcoat at 5micrograms per linear mm.

Example 9

[0171] Overcoating of a Drug-Loaded Stent with Polymer Having a VariableAreal Density.

[0172] A 10 mg/ml solution of phosphorylcholine-linked methacrylatepolymer (PC) is made in isobutanol. The linear travel speed of the stentunder the jet head is programmed to be 50% slower during the beginning25% of the stent length and the ending 25% of length. The jetting rateis not varied over the length of the stent. A total of 288 passes alongthe axial dimension of the stent, and over 1440 degrees of rotation aremade. Under these conditions, the stent obtains an increased amount ofPC on both ends of the stent compared to the middle regions.

Example 10

[0173] Drug-Loaded Stent Having a Variable Areal Density of Drug

[0174] A stock jetting solution of 20 mg/ml ABT-578+4 mg/mlphosphorylcholine-linked methacrylate polymer (PC) in isobutanol isprepared. The linear travel speed of the stent under the jet head isprogrammed to be 50% faster during the beginning 25% of the stent lengthand the ending 25% of length. The jetting rate is not varied over thelength of the stent. A total of 144 passes along the axial dimension ofthe stent and over 720 degrees of rotation are made. Under theseconditions, the stent obtains a decreased amount of ABT-578 on both endsof the stent compared to the middle regions.

[0175] It is understood that the foregoing detailed description andaccompanying examples are merely illustrative and are not to be taken aslimitations upon the scope of the invention, which is defined solely bythe appended claims and their equivalents. Various changes andmodifications to the disclosed embodiments will be apparent to thoseskilled in the art. For example, a charge-and-deflect dispenser can bereplaced with a drop-on-demand fluid jetter, or vice versa. Such changesand modifications, including without limitation those relating to thechemical structures, substituents, derivatives, intermediates,syntheses, formulations and or methods of use of the invention, can bemade without departing from the spirit and scope thereof.

What is claimed is:
 1. An interventional device for delivery of abeneficial agent, the interventional device comprising: a firstprosthesis to be deployed in a lumen; a second prosthesis configured tobe deployed in an overlapping relationship with the first prosthesis;the first prosthesis and the second prosthesis, in combination, definingat least one non-overlapping segment and an overlapping segment; and thefirst prosthesis and the second prosthesis loaded with beneficial agentto provide a controlled local areal density across a length of the firstprosthesis and the second prosthesis in combination.
 2. Theinterventional device of claim 1, wherein the controlled local arealdensity is uniform along the length of the first prosthesis and thesecond prosthesis in combination.
 3. The interventional device of claim1, wherein the controlled local areal density of beneficial agent isvaried along the length of the first prosthesis and the secondprosthesis in combination.
 4. The interventional device of claim 3,wherein the controlled local areal density of beneficial agent of thenon-overlapping segment is greater than the controlled local arealdensity of beneficial agent of the overlapping segment.
 5. Theinterventional device of claim 1, wherein the first prosthesis has afirst portion corresponding to the overlapping segment of the firstprosthesis and second prosthesis in combination; a second portioncorresponding to the at least one non-overlapping segment of the firstprosthesis and second prosthesis in combination; and at least one of thefirst portion and the second portion of the first prosthesis is loadedwith beneficial agent.
 6. The interventional device of claim 5, whereinthe first portion of the first prosthesis has a local areal density ofbeneficial agent different than the local areal density of beneficialagent of the second portion of first prosthesis.
 7. The interventionaldevice of claim 1, wherein the beneficial agent is selected from a groupconsisting of antithrombotics, anticoagulants, antiplatelet agents,anti-lipid agents, thrombolytics, antiproliferatives,anti-inflammatories, agents that inhibit hyperplasia, smooth muscle cellinhibitors, antibiotics, growth factor inhibitors, cell adhesioninhibitors, cell adhesion promoters, antimitotics, antifibrins,antioxidants, antineoplastics, agents that promote endothelial recovery,antiallergic substances, radiopaque agents, viral vectors, antisensecompounds, oligionucleotides, cell permeation enhancers, angiogenesisagents and combinations thereof.
 8. The interventional device of claim1, wherein a base material is applied to a selected surface of at leastone of the first prosthesis and the second prosthesis, and furtherwherein beneficial agent is introduced to the base material layer. 9.The interventional device of claim 1 wherein at least two differentbeneficial agents are loaded on at least one of the first prosthesis andthe second prosthesis.
 10. The interventional device of claim 1 whereinthe first prosthesis and second prosthesis in combination define abifurcated stent.
 11. An interventional device for delivery ofbeneficial agent, the device comprising: a prosthesis including atubular body when deployed in a lumen, the prosthesis having a firstportion and a second portion; the prosthesis at least partially loadedwith beneficial agent to define a controlled local areal density ofbeneficial agent, the controlled local areal density of beneficial agentat the first portion being different than at the second portion.
 12. Theinterventional device of claim 11, wherein the tubular body is definedby a plurality of interconnected structural members, the first portionof the prosthesis being a selected set of the interconnected structuralmembers.
 13. The interventional device of claim 12, wherein the selectedset of interconnected structural members define at least one ring-shapedelement extending around a circumference of the tubular body.
 14. Theinterventional device of claim 11, wherein the first portion of theprosthesis is defined by a first length of the tubular body and thesecond portion of the prosthesis is defined by a second length of thetubular body.
 15. The interventional device of claim 11, wherein thelocal areal density of beneficial agent is uniform across at least oneof the first portion and the second portion.
 16. The interventionaldevice of claim 11, wherein the local areal density of beneficial agentis varied across at least one of the first portion and the secondportion.
 17. The interventional device of claim 11, wherein thebeneficial agent of at least one of the first portion and the secondportion is loaded by a fluid-dispenser.
 18. The interventional device ofclaim 11, wherein the beneficial agent includes a binder prior to beingloaded by the fluid-dispenser.
 19. The interventional device of claim11, wherein the prosthesis includes a layer of a base material on asurface of the tubular body, the beneficial agent being loaded to thebase material layer.
 20. The interventional device of claim 11, whereinthe beneficial agent is selected from a group consisting ofantithrombotics, anticoagulants, antiplatelet agents, anti-lipid agents,thrombolytics, antiproliferatives, anti-inflammatories, agents thatinhibit hyperplasia, smooth muscle cell inhibitors, antibiotics, growthfactor inhibitors, cell adhesion inhibitors, cell adhesion promoters,antimitotics, antifibrins, antioxidants, antineoplastics, agents thatpromote endothelial recovery, antiallergic substances, radiopaqueagents, viral vectors, antisense compounds, oligionucleotides, cellpermeation enhancers, angiogenesis agents and combinations thereof. 21.The interventional device of claim 20, wherein the beneficial agent isselected from a group consisting of estradiol, dexamethasone, rapamycin,paclitaxel, and the rapamycinanalog-3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Hexadecahydro-9,27-dihydroxy-3-[(1R)-2-[(1S,3R,4R)-3-methoxy-4-tetrazol-1-yl)cyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone;23,27-Epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone.22. The interventional device of claim 11, wherein the beneficial agentincludes a solvent.
 23. An interventional device for delivery ofbeneficial agent, the device comprising: a prosthesis including atubular body when deployed in a lumen; the prosthesis at least partiallyloaded with a beneficial agent having a local areal density that isvaried along a selected portion of the tubular body.
 24. Theinterventional device of claim 23, wherein the local areal density ofbeneficial agent is varied as a continuous gradient along the selectedportion of the tubular body.
 25. The interventional device of claim 23,wherein the local areal density of beneficial agent is varied so as tohave a first local areal density of beneficial agent at at least one endsection of the prosthesis and a second local areal density of beneficialagent at an intermediate section of the prosthesis, the first localareal density being different than the second local areal density. 26.The interventional device of claim 25, wherein the first local arealdensity is less than the second local areal density.
 27. Theinterventional device of claim 23, wherein the local areal density ofbeneficial agent is varied to correspond with a location of a lesion inthe lumen when the prosthesis is deployed.
 28. The interventional deviceof claim 23, wherein the prosthesis includes a layer of a base materialon a surface of the tubular body, the beneficial agent being loaded tothe base material layer.
 29. The interventional device of claim 23,wherein the beneficial agent is selected from a group consisting ofantithrombotics, anticoagulants, antiplatelet agents, anti-lipid agents,thrombolytics, antiproliferatives, anti-inflammatories, agents thatinhibit hyperplasia, smooth muscle cell inhibitors, antibiotics, growthfactor inhibitors, cell adhesion inhibitors, cell adhesion promoters,antimitotics, antifibrins, antioxidants, antineoplastics, agents thatpromote endothelial recovery, antiallergic substances, radiopaqueagents, viral vectors, antisense compounds, oligionucleotides, cellpermeation enhancers, angiogenesis agents and combinations thereof. 30.The interventional device of claim 23, wherein the beneficial agentincludes a solvent.